Cyclopropenone derivatives

ABSTRACT

A novel cyclopropenone derivative (I) which possesses a potent inhibitory activity against thiol protease such as papain, cathepsin B, cathepsin H, cathepsin L, calpain or the like with excellent properties regarding oral absorbance, tissue transference and cell membrane permeability, and are clinically useful in the treatment of various diseases such as muscular dystrophy, amyotrophy. Also provided are a process for producing the compound (I) and a pharmaceutical composition containing the same.

FIELD OF THE INVENTION

The present invention relates to novel cyclopropenone derivatives. Moreparticularly, this invention relates to novel cyclopropenone derivativeshaving a potent inhibitory activity against thiol protease such aspapain, cathepsin B, cathepsin H, cathepsin L, calpain or the like.

BACKGROUND OF THE INVENTION

In accordance with the elucidation of the in vivo activity of thiolprotease such as papain, cathepsin B, cathepsin H, cathepsin L, calpainor the like, it has been found that their extraordinary hyperstheniacauses various diseases. Further, there is increasing the report whichshows thiol protease inhibitors are effective on such disease in animalmodels.

It is considered that thiol protease such as calpain, cathepsin B or thelike take part in the initial process such as disappearance of Z linethrough the decomposition of muscular fiber protein in the collapse ofskeletal muscle as seen in muscular disease such as muscular Dystrophy,amyotrophy or the like [Taisha (Metabolism), 25, 183 (1988)].Furthermore, E-64-d, namely a thiol protease inhibitor, has beenreported to have life-prolonging effect in experimental musculardystrophy hamster [Journal of Pharmacobio dynamics, 10, 678 (1987)].Accordingly, such thiol protease inhibitors are expected to be useful astherapeutic agents for the treatment of muscular dystrophy, amyotrophyor the like.

The main cause of the post-ischemic cellular disorder occurs duringischemic diseases such as cardiac infarction, stroke and the like isactive oxygen produced by xanthine oxidase. It has been reported that,during the ischemia, the increase in Ca²⁺ concentration results in theactivation of calpain which restrictively degrade xanthinedehydrogenase, a precursor of xanthine oxidase, to give xanthine oxidase[New England Journal of Medicine, 312, p. 159, (1985)]. It has also beenreported that the activation of calpain may directly cause the necrosisof myocardial cells or neurocytes [Saishin Igaku, 43, p. 783, (1988)].There have been reported that NCO-700, a calpain inhibitor, is effectiveon cardiac infarction when tested on animal models [ArzneimittelForschung/Drug Research, 36, p. 190, p. 671, (1986)], and that E-64-Cinhibits the degradation of microtubule-associated protein after thebrain ischemia [Brain Research, 526, p. 177, (1990)]. These reportsindicate that a calpain inhibitor can be useful for the treatment ofischemic diseases such as cardiac infarction, stroke and the like.

The cause of senile plaque which is found specifically in the brain ofpatients suffering from Alzheimer's disease is known to be theprecipitated amyloid, a protein produced by the decomposition of anamyloid precursor protein (APP). Although APP does not give amyloid as anormal metabolite, it may be converted into amyloid under an abnormalmetabolism where protease is extremely activated, and precipitated assenile plaque [Scientific American, (11), p. 40, (1991)]. Therefore,protease inhibitor is expected to be useful for the treatment ofAlzheimer's disease.

The activation of calpain has been observed in a brain trauma model ofrabbit [Neurochemical Research, 16, p. 483, (1991)]. It has also beenobserved, the administration of leupetin, a calpain inhibitor, canprotect axon in brain trauma models of rat [Journal of Neurosurgery, 65,p. 92, (1986)]. Thus, calpain inhibitors are considered to be useful forimproving the conscious disturbance or motor disturbance caused by braintrauma.

It has also been reported that myelin-associated protein exists indendrite of neurocytes is decomposed by calpain [Journal ofNeurochemistry, 47, p. 1007, (1986)], indicating that calpain inhibitorsmay be effective on diseases caused by the demyelination of neurocytessuch as multiple sclerosis, peripheral nervous neuropathy and the like.

The main cause of the turbidity during cataract is hydrolytic productsof a water-soluble protein crystallin by protease in lens. It has beenobserved the increase in calcium concentration in lens of cataractousanimal models and some of human cataract [Investigative Ophthalmology &Visual Science, 28, p. 1702, (1987); Experimental Eye Research, 34, p.413, (1982)]. The dominant protease contained in lens is calpain [Lensand Eye Toxicity Research, 6, p. 725, (1989)]. These facts indicate thatthe abnormal sthenia of calpain can be one the causes of cataract. Thereis a report that E-64, an inhibitor of calpain, is effective on cataractin animal models [Investigative Ophthalmology & Visual Science, 32, p.533, (1991)], indicating that calpain inhibitors can be useful in thetreatment of cataract.

Neutrophils, which is deeply associated to inflammation, show thedegranulation or production of superoxides in response to thestimulations by a chemotaxic factor or phorbol ester through a mechanismappeared to be mediated by protein kinase C (PKE-64 C). Calpainparticipates in the activation of PKC in the manner where it promotesthe degranulation and inhibits the production superoxides [Journal ofBiological Chemistry, 263, p. 1915, (1988)]. In another report, theconcentration of cathepsin B in macrophage in rat is 30 to 40 times thatof leukocytes and neutrophils, and the concentration of the enzyme ininflammatory macrophage is 6 times that of normal macrophages [Journalof Biochemistry, 98, p. 87, (1985)]. These facts indicate that thiolprotease inhibitors are useful as anti-inflammatory drugs.

The type I allergy reaction is mediated by immunoglobulin E (IgE)produced in the subject immunized with an antigen. Estatin A, a thiolprotease inhibitor, has been reported to specifically inhibit theproduction of IgE without affecting on the production of IgG [TheJournal of Antibiotics, 42, p. 1362, (1989)]. Accordingly, thiolprotease inhibitors are considered to be useful as antiallergic drugs.

In case of necrosis of hepatic cells, it is believed that impairment ofthe cell membrane leads to an increase in the permeability of Ca²⁺, anincrease in intracellular Ca²⁺ concentration, an activation of calpain,and, as the result, the decomposition of its substrate such as skeletalprotein takes place, which results in the death of cells. Accordingly, acalpain inhibitor can be used as a therapeutic agent for fulminanthepatitis.

Cathepsins such as cathepsin B and cathepsin L are involved indecomposition of bone collagen in osteoclast. It has been reported thatadministration of an inhibitor of cathepsins, E-64 or estatin A, to arat which has an enhanced bone destruction by administration ofparathyroid hormone leads to a decrease of calcium concentration andhydroxyproline concentration in blood [Biochemical and BiophysicalResearch Communication, 125, p. 441, (1984): Japanese Patent Publication(kokai) No. 218610/1990]. Accordingly, it is believed that an inhibitorof cathepsins can be a therapeutic agent for osteoporosis, hypercalcemiaand the like.

There exist, as a substrate for calpain, sex hormone receptors such asestrogen receptor and androgen receptor, and it is known that calpainactivates these receptors. Accordingly, it is considered that anabnormal sthenia of calpain causes a disease which is suspected to becaused by an abnormal activation of the sex hormone receptors, forexample, breast carcinoma, prostatic carcinoma or prostatomegaly. It isbelieved that an inhibitor for calpain can be a therapeutic agent forthe above disease.

Receptors for epidermal growth factor (EGF) are also considered to beactivated in association with the canceration of cells. It is known thatcalpain activates the EGF receptors as its substrate. Furthermore, ithas been reported that calpain is activated in cells which have beeninfected with adult T cell human leukocyte virus (ATLV/HTLV-1)[Seikagaku, 57, p. 1202, (1985)]. On the other hand, it is said thatcathepsin B is greatly involved in a process of cancer metastasisbecause it accelerates decomposition of collagen which is a importantstep for the cancer metastasis or directly decomposes collagen, andbecause it has a profound correlation with plasma membrane of neoplasticcells [Tumor Progression and Markers, p. 47, (1982); Journal ofBiological Chemistry, 256, p. 8536, (1984)]. These facts suggest that athiol protease inhibitor has an ability to suppress the growth of cancercells and prevent the metastasis of cancer.

Activation of platelet causes the aggregation thereof which is a causeof thrombus. It has been reported that an inhibitor of calpain, E-64-d,suppressed aggregation of platelet caused by thrombin [ThrombosisResearch, 57, p. 847, (1990)]. Accordingly, the inhibitor of calpain canbe used as an inhibitor against aggregation of platelet.

As described above, an abnormal sthenia of thiol protease causes variousdiseases and a validity of several thiol protease inhibitors in animalmodels has been reported. However, most of known inhibitors, forexample, epoxy succinate derivatives such as E-64 [Agricultural andBiological Chemistry, 42, p. 529, (1978)], E-64-d [Journal ofBiochemistry, 93, p. 1305, (1983)], NCO-700 [Japanese Patent Publication(kokai) No. 126879/1983], and estatins A and B [The Journal ofAntibiotics, 42, p. 1362, (1989)], or α-substituted ketone of a peptidesuch as chloromethyl ketone [Journal of Biochemistry, 99, p. 173,(1986)] and acyloxymethyl ketone [Biochemistry, 30, p. 4678, (1991)] areirreversible inhibitors. It is generally said that the irreversibleinhibitors are highly toxic because they are liable to react withnon-specifically to components consisting living body, other than targetenzymes. Therefore, there have been few compounds applicable to clinicaluse so far. Although peptidyl aldehydes such as leupeptin [The Journalof Antibiotics, 22, p. 183, (1969)] or carpeptine [Journal of EnzymeInhibition, 3, p. 195, (1990)] are known as reversible inhibitors, theyalso have problems in chemical and in vivo stabilities, cell membranepermeabilities and the like.

SUMMARY OF THE INVENTION

The present inventors investigated into various compounds with aim ofdeveloping reversible inhibitors against thiol protease, which haveexcellent properties concerning absorbance on oral administration,tissue distribution and cell membrane permeability, and have found thatcertain derivatives of cyclopropenone have such desired properties.

Thus, the present invention provides cyclopropenone derivatives ofgeneral formula (I): ##STR1## wherein R¹ is hydrogen atom, R¹² --CO--,R¹² --NH--CO-- or R¹² --SO₂ -- (in which R¹² is C₁ -C₂₀ alkyl groupoptionally substituted by one or more substituents selected from thegroup consisting of C₃ -C₁₅ cycloalkyl group, optionally substituted C₆-C₁₄ aryl group, C₃ -C₁₅ cycloalkyloxy group, optionally substituted C₆-C₁₄ aryloxy group, optionally substituted C₆ -C₁₄ arylthio group,optionally substituted C₆ -C₁₄ arylsulfonyl group, optionallysubstituted C₇ -C₂₀ aralkyloxy group, optionally substitutedheterocyclic group, oxo group, hydroxyl group, C₁ -C₁₀ alkoxycarbonylgroup and carboxyl group; C₃ -C₁₅ cycloalkyl group; optionallysubstituted C₆ -C₁₄ aryl group or optionally substituted heterocyclicgroup); R², R⁴ and R⁶ each is independently hydrogen atom or C₁ -C₁₀alkyl group optionally substituted by C₁ -C₅ alkoxy group or C.sub. 1-C₅ alkylthio group; R³, R₅ and R⁷ each is independently hydrogen atom,C₁ -C₂₀ alkyl group optionally substituted by C₃ -C₁₀ cycloalkyl group,C₃ -C₁₀ cycloalkyl group or optionally substituted C₇ -C₂₀ aralkylgroup; R₈ is hydrogen atom or C₁ -C₂₀ alkyl group; R⁷ and R⁶ takentogether may form C₃ C₁₅ cycloalkyl group; R⁹ is hydroxyl group or C₂-C₁₀ acyloxy group; R¹⁰ is hydrogen atom; R⁹ and R¹⁰ taken together mayform oxo group; R¹¹ is hydrogen atom, C₁ -C₂₀ alkyl group optionally.substituted by C₃ -C₁₅ cycloalkyl group, C₃ -C₁₅ cycloalkyl group, C₂-C₂₀ alkenyl group, optionally substituted C₆ -C₁₄ aryl group,optionally substituted C₇ -C₂₀ aralkyl group, optionally substitutedheterocyclic group or --C(R¹³)(R¹⁴)--OH (in which R¹³ and R¹⁴ each isindependently hydrogen atom, C₁ -C₂₀ alkyl group, optionally substitutedC₇ -C₂₀ aralkyl group or optionally substituted C₆ -C₁₄ aryl group, orR₁₃ and R¹⁴ taken together may form C₃ -C₁₅ cycloalkyl group); and n is0 or 1 or pharmaceutically acceptable salts thereof.

The present invention also provides a pharmaceutical compositionscontaining, as an active ingredient, a cyclopropenone derivative offormula (I) or a salt thereof.

The present invention also provides a process for the preparation ofcyclopropenone derivatives of formula (I).

DETAILED DESCRIPTION OF THE INVENTION Definition

For the purpose of the invention the following terms used herein aredefined as follows:

In the definition of R¹² : examples of C₁ -C₂₀ alkyl group includemethyl group, ethyl group, propyl group, isopropyl group, butyl group,isobutyl group, sec-butyl group, tert-butyl group, pentyl group,isopentyl group, neopentyl group, tert-pentyl group, hexyl group,isohexyl group, heptyl group, octyl group, nonyl group, decyl group,undecyl group, dodecyl group, tridecyl group, tetradecyl group,pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group,nonadecyl group, icosyl group and the like. Such an alkyl group may beoptionally substituted by one or more substituents selected from thegroup consisting of C₃ -C₁₅ cycloalkyl group such as cyclopropyl group,cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptylgroup, cyclooctyl group, cyclononyl group, cyclodecyl group,cycloundecyl group, cyclododecyl group, cyclotridecyl group,cyclotetradecyl group, cyclopentadecyl group or the like; C₆ -C₁₄ arylgroup such as phenyl group, naphthyl group, anthryl group; C₃ -C₁₅cycloalkyloxy group such as cyclopropyloxy group, cyclobutyloxy group,cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group;cyclooctyloxy group, cyclodecyloxy group, cyclopentadecyloxy group orthe like; C₆ -C₁₄ aryloxy group such as phenoxy group, 1-naphthoxygroup, 2-naphthoxy group or the like; C₆ -C₁₄ arylthio group such asphenylthio group, 1-naphthylthio group, 2-naphthylthio group or thelike; C₆ -C₁₄ arylsulfonyl group such as phenylsulfonyl group,1-naphthylsulfonyl group, 2-naphthylsulfonyl group or the like; C₇ -C₂₀aralkyloxy group such as benzyloxy group, 1-phenylethoxy group,2-phenylethoxy group, 1-phenylpropoxy group, 2-phenylpropoxy group,3-phenylpropoxy group, 4-phenylbutoxy group, 5-phenylpentyloxy group,1-naphthylmethoxy group, 2-naphthylmethoxy group, 1-(1-naphthyl)ethoxygroup, 2-(1-naphthyl)ethoxy group, 1-(2-naphthyl)ethoxy group,2-(2-naphthyl)ethoxy group or the like; 5-10 membered heterocyclic groupcontaining 1 to 4 hetero atoms selected from oxygen atom, sulfur atomand nitrogen atom to form a ring such as furan ring, dihydrofuran ring,tetrahydrofuran ring, pyran ring, dihydropyran ring, tetrahydropyranring, benzofuran ring, isobenzofuran ring, chromene ring, chroman ring,isochroman ring, thiophene ring, benzothiophene ring, pyrrole ring,pyrroline ring, pyrrolidine ring, imidazole ring, imidazoline ring,imidazolidine ring, pyrazole ring, pyrazoline ring, pyrazolidine ring,triazole ring, tetrazole ring, pyridine ring, pyridine oxide ring,piperidine ring, pyrazine ring, piperazine ring, pyrimidine ring,pyridazine ring, indolidine ring, indole ring, indoline ring, isoindolering, isoindoline ring, indazole ring, benzoimidazole ring, purine ring,quinolidine ring, quinoline ring, phthalazine ring, naphthylidine ring,quinoxaline ring, quinazoline ring, cinnoline ring, pteridine ring,oxazole ring, oxazolidine ring, isoxazole ring, isoxazolidine ring,thiazole ring, thiazolidine ring, isothiazole ring, isothiazolidinering, dioxane ring, dithian ring, morpholine ring, thiomorpholine ringor the like; C₁ -C₁₀ alkoxycarbonyl group such as methoxycarbonyl group,ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group,butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonylgroup, pentyloxycarbonyl group, hexyloxycarbonyl group,heptyloxycarbonyl group, octyloxycarbonyl group, decyloxycarbonyl groupor the like; oxo group; hydroxyl group and carboxyl group. Examples ofC₃ -C₁₅ cycloalkyl group, C₆ -C₁₄ aryl group and heterocyclic group arethe same as those illustrated in the definition of the substituents ofC₁ -C₂₀ alkyl group.

In the definition of R², R⁴ and R⁶, examples of C₁ -C₁₀ alkyl groupinclude methyl group, ethyl group, propyl group, isopropyl group, butylgroup, isobutyl group, sec-butyl group, tert-butyl group, pentyl group,isopentyl group, neopentyl group, tert-pentyl group, hexyl group,isohexyl group, heptyl group, octyl group, nonyl group, decyl group andthe like. Such an alkyl group may be optionally substituted by C₁ -C₅alkoxy group such as methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group,pentyloxy group, isopentyloxy group or the like or C₁ -C₅ alkylthiogroup such as methylthio group, ethylthio group, propylthio group,isopropylthio group, butylthio group, isobutylthio group, tert-butylthiogroup, pentylthio group, isopentylthio group or the like.

In the definition of R³, R⁵ and R⁷, examples of C₁ -C₂₀ alkyl groupoptionally substituted by C₃ -C₁₀ cycloalkyl group and C₃ -C₁₀cycloalkyl group are the same as those illustrated in the definition ofR¹² except that cycloalkyl group is C₃ -C₁₀ cycloalkyl group. Examplesof C₇ -C₂₀ aralkyl group are benzyl group, 1-phenethyl group,2-phenethyl group, 1-phenylpropyl group, 2-phenylpropyl group,3-phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group,1-naphthylmethyl group, 2-naphthylmethyl group, 1-(1-naphthyl)ethylgroup, 1-(2-naphthyl)ethyl group, 2-(1-naphthyl)ethyl group,2-(2-naphthyl)ethyl group and the like.

In the definition of R⁶, examples of C₁ -C₂₀ alkyl group are the same asthose illustrated in the definition of R¹².

Examples of C₃ -C₁₅ cycloalkyl group which R⁷ and R⁸ taken together mayform are the same as those illustrated in the definition of R¹².

In the definition of R⁹ examples of C₂ -C₁₀ acyloxy group arealkylcarbonyloxy group such as acetoxy group, propionyloxy group,butyryloxy group, valeryloxy group and the like.

In the definition of R¹¹ examples of C₁ -C₂₀ alkyl group optionallysubstituted by C₃ -C₁₅ cycloalkyl group, C₃ -C₁₅ cycloalkyl group, C₆-C₁₄ aryl group and heterocyclic group are the same as those illustratedin the definition of R¹², and examples of C₂ -C₂₀ alkenyl group arevinyl group, 1-propenyl group, allyl group, 1-butenyl group, 2-butenylgroups 3-butenyl groups 1-pentenyl group, 2-pentenyl group, 3-pentenylgroup, 4-pentenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenylgroup, 4-hexenyl group, 5-hexenyl group, 1-heptenyl group, 1-octenylgroup, 1-nonenyl group, 1-decenyl groups 1-dodecenyl group,1-pentadecenyl group and the like. Examples of C₇ -C₂₀ aralkyl group arethe same as those illustrated in the definition of R³, R₅ and R⁷.

In the definition of R¹³ and R¹⁴, examples of C₁ -C₂₀ alkyl group and C₆-C₁₄ aryl group are the same as those illustrated in the definition ofR¹² and examples of C₇ -C₂₀ aralkyl group are the same as thoseillustrated in the definition of R³, R⁵ and R⁷.

Examples of C₃ -C₁₅ cycloalkyl group which R¹³ and R¹⁴ taken togethermay form are the same as those illustrated in the definition of R¹².

The aromatic and the heterocyclic groups which positioned at the end ofeach substituent as defined in the above may optionally have one or moresubstituents selected from the group consisting of halogen atom such asfluorine atom, chlorine atom, bromine atom or the like; C₁ C₅ alkylgroup such as methyl group, ethyl group, propyl group, isopropyl group,butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentylgroup, isopentyl group, neopentyl group or the like; trifluoromethylgroup; C₁ -C₅ alkoxy group such as methoxy group, ethoxy group, propoxygroup, isopropoxy group, butoxy group, isobutoxy group, tert-butoxygroup, pentyloxy group, isopentyloxy group or the like; C₁ -C₅alkylenedioxy group such as methylenedioxy group, ethylenedioxy group,propylenedioxy group or the like; hydroxyl group; C₂ -C₆alkylcarbonyloxy group such as acetoxy group, propionyloxy group,butyryloxy group, valeryloxy group or the like; carboxyl group; C₂ -C₆alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonylgroup, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonylgroup, isobutoxycarbonyl group, tert-butoxycarbonyl group,pentyloxycarbonyl group or the like; oxo group; C₂ -C₆ alkylcarbonylsuch as acetyl group, propionyl group, butyryl group, valeryl group orthe like; amino group; C₂ C₆ monoalkylamino group such as methylaminogroup, ethylamino group, propylamino group, isopropylamino group,butylamino group, isobutylamino group, tert-butylamino group,pentylamino group, isopentylamino group or the like; C₂ C₁₀ dialkylaminogroup such as dimethylamino group, ethylmethylamino group, diethylaminogroup, methylpropylamino group, diisopropylamino group or the like; C₂-C₆ alkylcarbonylamino group such as acetylamino group, propionylaminogroup, isopropionylamino group, butyrylamino group, valerylamino groupor the like; carbamoyl group; C₂ -C₆ alkylcarbamoyl group such asmethylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group,isopropylcarbamoyl group, butylcarbamoyl group, tert-butylcarbamoylgroup, pentylcarbamoyl group or the like; C₆ -C₁₄ aryl group such asphenyl group, naphthyl group or the like; and trimethylsilyl group.

Although all the compound (I) as defined above are useful for thepurpose of the invention, there are some preferable compounds. Thus,compounds (I) included in the following [Group A] are preferable, andamong compounds of [Group A], those belong to [Group B] are particularlypreferred.

Group A

Compound of formula ( I ) , wherein R¹ is hydrogen atom, R¹² --CO--, R¹²--O--CO--, R¹² --NH--CO-- or R¹² --SO₂ -- (in which R¹² is C₁ -C₂₀ alkylgroup optionally substituted by one or more substituents selected fromthe group consisting of C₃ -C₁₅ cycloalkyl group, optionally substitutedC₆ -C₁₄ aryl group, optionally substituted C₆ -C₁₄ aryloxy group,optionally substituted C₆ -C₁₄ arylthio groups optionally substituted C₇-C₂₀ aralkyloxy group, optionally substituted heterocyclic group, oxogroup, hydroxyl group, C₁ -C₁₀ alkoxycarbonyl group and carboxyl group:C₃ -C₁₅ cycloalkyl group, optionally substituted C₆ -C₁₄ aryl group oroptionally substituted heterocyclic group); R², R⁴ and R⁶ each isindependently hydrogen atom, C₁ -C₁₀ alkyl group optionally substitutedby C₁ -C₅ alkylthio group; R³, R⁵ and R⁷ each is hydrogen atom, C₁ -C₂₀alkyl group optionally substituted by C₃ -C₁₀ cycloalkyl group, C₃ -C₁₀cycloalkyl group or optionally substituted C₇ -C₂₀ aralkyl group; R⁸ ishydrogen atom or C₁ -C₂₀ alkyl group; R⁹ is hydroxyl group or C₂ -C₁₀acyloxy group; R¹⁰ is hydrogen atom; or R⁹ and R¹⁰ taken together mayform oxo group; R¹¹ is hydrogen atom, C₁ -C₂₀ alkyl group optionallysubstituted by C₃ -C₁₅ cycloalkyl group, C₃ -C₁₅ cycloalkyl group, C₂-C₂₀ alkenyl group, optionally substituted C₆ -C₄ aryl group, C₇ -C₂₀aralkyl group, optionally substituted heterocyclic group, or--C(R¹³)(R¹⁴)--OH (in which R¹³ and R¹⁴ each is independently hydrogenatom, C₁ -C₂₀ alkyl group or C₆ -C₁₄ aryl group; and n is 0 or 1.

Group B

Compound of formula (I), wherein R¹ is R¹² --CO--, R¹² --O--CO--, R¹²NH--CO--, R¹² --SO₂ -- (in which R¹² is C₁ -C₁₅ alkyl group optionallysubstituted by one or more substituents selected from the groupconsisting of C₃ -C₁₀ cycloalkyl group, optionally substituted C₆ -C₆-C₁₄ aryloxy group, optionally substituted C₆ -C₁₄ arylthio group,optionally substituted C₇ -C₂₀ aralkyloxy group, optionally substitutedheterocyclic group and oxo group; C₃ -C₁₀ cycloalkyl group; optionallysubstituted C₆ -C₁₀ aryl group or optionally substituted heterocyclicgroup); R², R⁴ and R⁶ each is independently hydrogen atom or C₁ -C₁₀alkyl group; R³, R⁵ and R⁷ each is independently hydrogen atom, C₁ -C₁₅alkyl group optionally substituted by C₃ -C₁₀ cycloalkyl group, C₃ C₁₀cycloalkyl group or optionally substituted C.sub. 7 -C₂₀ aralkyl group;R⁸ is hydrogen atom; R⁹ is hydroxyl group or C₂ -C₁₀ acyloxy group;R^(io) is hydrogen atom; and R¹¹ is hydrogen atom, C₁ -C₁₅ alkyl groupoptionally substituted by C₃ -C₁₀ cycloalkyl group, C₃ -C₁₀ cycloalkylgroup, C₇ -C₂₀ aralkyl group, optionally substituted C₆ -C₁₀ aryl groupor optionally substituted heterocyclic group.

Furthermore, among the compounds in [Group B], the compounds belong to[Group C] and [Group D] are preferred and of the compounds in [Group C],those in [Group E] and [Group F] are more preferred. Among compounds in[Group D], those in [Group G] are more preferred.

Group C

Compounds of formula (I), wherein R¹² is R¹² --CO--, R¹² --CO-- or R¹²--NC_(--CO--) (in which R¹² is C₁ -C₁₅ alkyl group optionallysubstituted by one or more substituents selected from the groupconsisting of C₃ -C₁₀ cycloalkyl group, optionally substituted C₆ -C₁₄aryl group, optionally substituted C₆ -C₁₄ aryloxy group, optionallysubstituted C₆ -C₁₄ arylthio group, optionally substituted C₇ -C₂₀aralkyloxy group, optionally substituted heterocyclic group and oxogroup; or optionally substituted C₆ -C₁₀ aryl group); R², R⁴ and R⁶ eachis independently hydrogen atom or C₁ -C₁₀ alkyl group; R³, R⁵ and R⁷each hydrogen atom, C₁ -C₁₅ alkyl group optionally substituted by C₃-C₁₀ cycloalkyl group, C₃ -C₁₀ cycloalkyl group or C₁ -C₂₀ aralkylgroup; R⁸ is hydrogen atom; R⁹ is hydroxyl group or C₂ -C₁₀ acyloxygroup; R¹⁰ is hydrogen atom; and R¹¹ is hydrogen atom, C₁ -C₁₅ alkylgroup optionally substituted by C₃ -C₁₀ cycloalkyl group, C₃ -C₁₀cycloalkyl group, C₇ -C₂₀ aralkyl group, optionally substituted C₆ -C₁₀aryl group or optionally substituted heterocyclic group.

Group D

Compounds of formula (I), wherein R¹ is R¹² --SO₂ -- (in which R¹² is C₁-C₁₅ alkyl group optionally substituted by one or more substituentsselected from the group consisting of C₃ -C₁₀ cycloalkyl group,optionally substituted C₆ -C₁₄ aryl group, optionally substituted C₆-C₁₀ aryloxy group, C₆ -C₁₄ arylthio group, optionally substituted C₇-C₂₀ aralkyloxy group, optionally substituted heterocyclic group and oxogroup; C₃ -C₁₀ cycloalkyl group; optionally substituted C₆ -C₁₀ arylgroup or optionally substituted heterocyclic group); and R¹¹ is hydrogenatom, optionally substituted C₆ -C₁₀ aryl group or optionallysubstituted heterocyclic group.

Group E

Compounds of formula (I), wherein R¹ is R¹² --O--CO-- (in which R¹² isC₁ -C₁₅ alkyl group optionally substituted by one or more substituentsselected from the group consisting of C₃ -C₁₀ cycloalkyl group, C₆ -C₁₄aryl group and heterocyclic group or C_(C) ₃ -C₁₀ cycloalkyl group); R⁴and R⁶ each is hydrogen atom; R¹¹ is hydrogen atom, C₁ -C₁₅ alkyl groupoptionally substituted by C₃ -C₁₀ cycloalkyl group, C₃ -C₁₀ cycloalkylgroup, C₇ -C₂₀ aralkyl group or C₆ -C₁₀ aryl group; and n is 0.

Group F

Compound of formula (I), wherein R¹ is R¹² --O--CO-- (in which R¹² is C₁-C₁₅ alkyl group optionally substituted by one or more substituentsselected from the group consisting of C₃ -C₁₀ cycloalkyl group, C₆ -C₁₄aryl group, and heterocyclic group); R^(C) ₄ and R⁶ each is hydrogenatom; R⁵ and R⁷ each is independently hydrogen atom, C₁ -C₁₅ alkyl groupoptionally substituted by C₃ -C₁₀ cycloalkyl group or C₇ -C₂₀ aralkylgroup; R⁹ is hydroxyl group; R¹⁰ is hydrogen atom; R¹¹ is optionallysubstituted heterocyclic group; and n is 0.

Group G

Compounds of formula (I), wherein R¹² is optionally substituted C₆ -C₁₀aryl group or optionally substituted heterocyclic group.

As will be understood from the structure, the cyclopropenone derivativesof formula (I) can form pharmaceutically acceptable salts thereof.Examples of such salts include, when an acidic group is present, metalsalts such as lithium salt, sodium salt, potassium salt, magnesium salt,calcium salt or the like and ammonium salts such as ammonium salt,methylammonium salt, dimethylammonium salt, trimethylammonium salt,dicyclohexylammonium salt or the like and, when a basic group ispresent, mineral acid salts such as hydrochloride, hydrobromide,sulfate, nitrate, phosphate or the like and organic acid salts such asmethanesulfonate, benzene-sulfonate, p-toluenesulfonate, acetate,propionate, tartrate, fumarate, maleate, malate, oxalate, succinate,citrate, benzoate, mandelate, cinnamate, lactate or the like.

Considering the stereochemistry of the sites of double bond existing inthe cyclopropenone derivatives of formula (I), these compounds can take(E), (Z) or (EZ) form. As to the stereochemistry of asymmetric carbon,compounds (I) can be independently in (R), (S) or (RS) form.

The following Tables 1 and 2 shows examples of the cyclopropenonederivatives of formula (I) in case of n=0;and n=1, respectively.

      TABLE 1 (n = 0) Compd.          No. R.sup.1 R.sup.4 R.sup.5 R.sup.6     R.sup.7 R.sup.8 R.sup.9 R.sup.10 R.sup.11      1     ##STR2##      H      ##STR3##      H CH.sub.3 H OH H H      2     ##STR4##      H      ##STR5##      H CH.sub.3 H OH H H      3     ##STR6##      H      ##STR7##      H CH.sub.3 H OH H H      4     ##STR8##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H H   5      ##STR9##      H CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.3 CH(CH.sub.3).sub.2 H OH H H   6      ##STR10##      CH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H H   7      ##STR11##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H H   8      ##STR12##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H H   9      ##STR13##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H H    10      ##STR14##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H OH H H     11      ##STR15##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H OH H H     12      ##STR16##      H      ##STR17##      H CH.sub.2 CH(CH.sub.3).sub.2 H OH H H      13     ##STR18##      H CH.sub.3 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H OH H H      14     ##STR19##      H CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H OH H H     15      ##STR20##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H H      16     ##STR21##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H H   17 H H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2     CH.sub.3 H OH H H      18     ##STR22##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H H      19     ##STR23##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H H      20     ##STR24##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H      ##STR25##      H H      21     ##STR26##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.3 CH.sub.3 OH H H      22     ##STR27##      H      ##STR28##      H CH.sub.3 CH.sub.3 OH H H      23     ##STR29##      H      ##STR30##      H CH.sub.3 CH.sub.3      ##STR31##      H      24     ##STR32##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2     CH.sub.2 OH H H      25     ##STR33##      H CH(CH.sub.3).sub.2 H      ##STR34##      H OH H H      26     ##STR35##      H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR36##      H OH H H      27     ##STR37##      H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR38##      H OH H H      28     ##STR39##      H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR40##      H OH H H      29     ##STR41##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.3 H OH H CH.sub.3      30     ##STR42##      H      ##STR43##      H CH.sub.3 H OH H CH.sub.3      31     ##STR44##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H CH.sub.3   32      ##STR45##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H OH H     CH.sub.3      33     ##STR46##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H CH.sub.3      34     ##STR47##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H CH.sub.3   35 H H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2     CH.sub.2 CH.sub.3 H OH H CH.sub.3      36     ##STR48##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H CH.sub.3      37     ##STR49##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H CH.sub.3      38     ##STR50##      H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR51##      H OH H CH.sub.3      39     ##STR52##      H      ##STR53##      H CH.sub.3 H OH H CH.sub.2 CH.sub.3      40     ##STR54##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H OH H     CH.sub.2 CH.sub.3      41     ##STR55##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H CH.sub.2 CH.sub.3      42     ##STR56##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H OH H     CH.sub.2 CH(CH.sub. 3).sub.2      43     ##STR57##      H      ##STR58##      H CH.sub.3 H OH H CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2      44     ##STR59##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2      45     ##STR60##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR61##      46     ##STR62##      H      ##STR63##      H CH.sub.3 H OH H      ##STR64##      47     ##STR65##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR66##      48     ##STR67##      H      ##STR68##      H CH.sub.3 H OH H      ##STR69##      49     ##STR70##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H OH H      ##STR71##      50     ##STR72##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR73##      51     ##STR74##      H      ##STR75##      H CH.sub.3 H OH H      ##STR76##      52     ##STR77##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR78##      53     ##STR79##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR80##      54     ##STR81##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR82##      55     ##STR83##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR84##      56     ##STR85##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR86##      57     ##STR87##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR88##      58     ##STR89##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR90##      59     ##STR91##      H      ##STR92##      H CH.sub.3 H OH H      ##STR93##      60     ##STR94##       H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR95##      61     ##STR96##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR97##      62     ##STR98##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR99##      63     ##STR100##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH.sub.3 H OH H     ##STR101##      64     ##STR102##      H      ##STR103##      H CH.sub.3 H OH H      ##STR104##      65     ##STR105##      H      ##STR106##      H CH.sub.3 H OH H      ##STR107##      66     ##STR108##      H H H CH(CH.sub.3).sub.2 H OH H      ##STR109##      67     ##STR110##      H CH.sub.3 H CH(CH.sub.3).sub.2 H OH H      ##STR111##      68     ##STR112##      H CH.sub.3 H CH(CH.sub.3).sub.2 H OH H      ##STR113##      69     ##STR114##      H CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR115##      70     ##STR116##      H CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR117##      71     ##STR118##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR119##      72     ##STR120##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR121##      73     ##STR122##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR123##      74     ##STR124##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR125##      75     ##STR126##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR127##      76     ##STR128##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR129##      77     ##STR130##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR131##      78     ##STR132##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H     ##STR133##      H      ##STR134##      79     ##STR135##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H     ##STR136##      ##STR137##      80     ##STR138##      H CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.3 CH(CH.sub.3).sub.2 H OH H      ##STR139##      81     ##STR140##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR141##      82     ##STR142##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR143##      83     ##STR144##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR145##      84     ##STR146##      H CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.3 CH(CH.sub.3).sub.2 H OH H      ##STR147##      85     ##STR148##      CH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR149##      86     ##STR150##      CH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.3 CH(CH.sub.3).sub.2 H OH H      ##STR151##      87     ##STR152##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR153##      88     ##STR154##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR155##      89     ##STR156##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR157##      90     ##STR158##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR159##      91     ##STR160##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR161##      92     ##STR162##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR163##      93     ##STR164##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR165##      94     ##STR166##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR167##      95     ##STR168##      H CH.sub.2      CH(CH.sub.3).sub.2 H  CH(CH.sub.3).sub.2 H OH H     ##STR169##      96     ##STR170##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR171##      97     ##STR172##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR173##      98     ##STR174##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR175##      99     ##STR176##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR177##      100     ##STR178##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR179##      101     ##STR180##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR181##      102     ##STR182##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR183##      103     ##STR184##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR185##      104     ##STR186##       H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR187##       105 H H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR188##      106     ##STR189##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR190##      107     ##STR191##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR192##      108     ##STR193##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR194##      109     ##STR195##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR196##      110     ##STR197##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR198##      ##STR199##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR200##      112     ##STR201##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR202##      113     ##STR203##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR204##      114     ##STR205##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR206##      115     ##STR207##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub. 2 H OH H     ##STR208##      116     ##STR209##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR210##      117     ##STR211##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR212##      118     ##STR213##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR214##      119     ##STR215##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR216##      120     ##STR217##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR218##      121     ##STR219##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR220##      122     ##STR221##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR222##      123     ##STR223##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR224##      124     ##STR225##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR226##      125     ##STR227##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR228##      126     ##STR229##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR230##      127     ##STR231##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR232##      128     ##STR233##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR234##      129     ##STR235##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR236##      130     ##STR237##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR238##      131     ##STR239##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR240##      132     ##STR241##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR242##      133     ##STR243##      H CH.sub.2      CH(CH.sub.3).sub.3 H CH(CH.sub.3).sub.2 H OH H     ##STR244##      134     ##STR245##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR246##      135     ##STR247##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR248##      136     ##STR249##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR250##      137     ##STR251##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR252##      138     ##STR253##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR254##      139     ##STR255##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR256##      140     ##STR257##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR258##      141     ##STR259##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR260##      142     ##STR261##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR262##      143     ##STR263##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR264##      144     ##STR265##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR266##      145     ##STR267##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3 ).sub.2 H OH H     ##STR268##      146     ##STR269##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR270##      147     ##STR271##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR272##      148     ##STR273##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR274##      149     ##STR275##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR276##      150     ##STR277##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR278##      151     ##STR279##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR280##      152     ##STR281##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR282##      153     ##STR283##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR284##      154     ##STR285##      H CH.sub.2      CH(CH.sub.3 ).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR286##      155     ##STR287##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR288##      156     ##STR289##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR290##      157     ##STR291##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR292##      158     ##STR293##      H CH.sub.2      CH(CH.sub.3).sub. 2 H CH(CH.sub.3).sub.2 H OH H     ##STR294##      159     ##STR295##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR296##      160     ##STR297##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR298##      161     ##STR299##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR300##      162     ##STR301##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR302##      163     ##STR303##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR304##      164     ##STR305##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR306##      165     ##STR307##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR308##      166     ##STR309##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR310##      167     ##STR311##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR312##      168     ##STR313##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR314##      169     ##STR315##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR316##      170     ##STR317##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR318##      171     ##STR319##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR320##      172     ##STR321##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR322##      173     ##STR323##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR324##      174     ##STR325##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR326##      175     ##STR327##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR328##      176     ##STR329##      H  CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR330##      177     ##STR331##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR332##      178     ##STR333##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR334##      179     ##STR335##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR336##      180     ##STR337##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR338##      181     ##STR339##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR340##      182     ##STR341##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR342##      183     ##STR343##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR344##      184     ##STR345##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR346##      185     ##STR347##      H CH.sub. 2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR348##      186     ##STR349##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR350##      187     ##STR351##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR352##      188     ##STR353##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR354##      189     ##STR355##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR356##      190     ##STR357##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR358##      191     ##STR359##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR360##      192     ##STR361##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR362##      193     ##STR363##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR364##      194     ##STR365##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR366##      195     ##STR367##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR368##      196     ##STR369##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR370##      197     ##STR371##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR372##      198     ##STR373##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR374##      199     ##STR375##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR376##      200     ##STR377##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR378##      201     ##STR379##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR380##      202     ##STR381##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR382##      203     ##STR383##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR384##      204     ##STR385##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR386##      205     ##STR387##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR388##      206     ##STR389##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR390##      207     ##STR391##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR392##      208     ##STR393##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR394##      209     ##STR395##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR396##      210     ##STR397##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR398##      211     ##STR399##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR400##      212     ##STR401##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR402##      213     ##STR403##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR404##      214     ##STR405##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR406##      215     ##STR407##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR408##      216     ##STR409##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR410##      217     ##STR411##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR412##      218     ##STR413##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR414##      219     ##STR415##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR416##      220     ##STR417##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR418##      ##STR419##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR420##      222     ##STR421##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR422##      223     ##STR423##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR424##      224     ##STR425##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR426##      225     ##STR427##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR428##      226     ##STR429##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR430##      227     ##STR431##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR432##      228     ##STR433##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR434##      229     ##STR435##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR436##      230     ##STR437##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR438##      231     ##STR439##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR440##      232     ##STR441##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR442##      233     ##STR443##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR444##      234     ##STR445##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR446##      235     ##STR447##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR448##      236     ##STR449##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR450##      237     ##STR451##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR452##      238     ##STR453##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR454##      239     ##STR455##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR456##      240     ##STR457##      H CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.3 CH(CH.sub.3).sub.2 H OH H      ##STR458##      241     ##STR459##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H     ##STR460##      H      ##STR461##               242     ##STR462##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H     ##STR463##      ##STR464##                 243     ##STR465##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR466##      244     ##STR467##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR468##      245     ##STR469##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR470##      246     ##STR471##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR472##      247     ##STR473##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR474##      248     ##STR475##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR476##      249     ##STR477##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR478##      250     ##STR479##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR480##      251     ##STR481##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR482##      252     ##STR483##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR484##      253     ##STR485##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR486##      254     ##STR487##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR488##      255     ##STR489##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR490##      256     ##STR491##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR492##      257     ##STR493##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR494##      258     ##STR495##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR496##      259     ##STR497##      H CH.sub.2      CH(CH.sub. 3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR498##      260     ##STR499##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR500##      261     ##STR501##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR502##      262     ##STR503##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR504##      263     ##STR505##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR506##      264     ##STR507##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR508##      265     ##STR509##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR510##      266     ##STR511##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR512##      267     ##STR513##      H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH(CH.sub.3).sub.2 H OH H      ##STR514##      268     ##STR515##      H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H CH(CH.sub.3).sub.2 H OH H      ##STR516##      269     ##STR517##      H      ##STR518##      H CH(CH.sub.3).sub.2 H OH H      ##STR519##      270     ##STR520##      H      ##STR521##      H CH(CH.sub.3).sub.2 H OH H      ##STR522##      271     ##STR523##      H      ##STR524##      H CH(CH.sub.3).sub.2 H OH H      ##STR525##      272 H H     ##STR526##      H CH(CH.sub.3).sub.2 H OH H      ##STR527##      273     ##STR528##      H      ##STR529##      H CH(CH.sub.3).sub.2 H OH H      ##STR530##      274     ##STR531##      H      ##STR532##      H CH(CH.sub.3).sub.2 H OH H      ##STR533##      275     ##STR534##      H      ##STR535##      H CH(CH.sub.3).sub.2 H OH H      ##STR536##      276     ##STR537##      H      ##STR538##      H CH(CH.sub.3).sub.2 H OH H      ##STR539##      277     ##STR540##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub. 2 CH(CH.sub.3).sub.2 H OH H      ##STR541##      278     ##STR542##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H OH H      ##STR543##      279     ##STR544##      H CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H OH H      ##STR545##      280     ##STR546##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR547##      281     ##STR548##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR549##      282     ##STR550##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR551##      283     ##STR552##      H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR553##      H OH H      ##STR554##      284     ##STR555##      H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR556##      H OH H      ##STR557##      285     ##STR558##      H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR559##      H OH H      ##STR560##      286     ##STR561##      H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR562##      H OH H      ##STR563##      287     ##STR564##      H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR565##      H OH H      ##STR566##      288     ##STR567##      H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR568##      H OH H      ##STR569##      289     ##STR570##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH.sub.3 CH.sub.3 OH H     ##STR571##      290     ##STR572##      H CH.sub.2      CH(CH.sub.3).sub. 2 H CH.sub.3 CH.sub.3 OH H     ##STR573##      291     ##STR574##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH.sub.3 CH.sub.3 OH H     ##STR575##      292     ##STR576##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH.sub.3 CH.sub.3 OH H     ##STR577##      293     ##STR578##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH.sub.3 CH.sub.3 OH H     ##STR579##       294 H H CH.sub.2      CH(CH.sub.3).sub.2 H CH.sub.3 CH.sub.3 OH H     ##STR580##      295     ##STR581##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH.sub.3 CH.sub.3 OH H     ##STR582##      296     ##STR583##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH.sub.3 CH.sub.3 OH H     ##STR584##      297     ##STR585##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH.sub.3 CH.sub.3 OH H     ##STR586##      298     ##STR587##      CH.sub.2 SCH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.3 CH.sub.3 OH H      ##STR588##               299     ##STR589##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH.sub. 3 CH.sub.3     ##STR590##      ##STR591##      300     ##STR592##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH.sub.3 CH.sub.3     ##STR593##      ##STR594##      301     ##STR595##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH.sub.3 CH.sub.3     ##STR596##      ##STR597##               302     ##STR598##      H CH.sub.2      CH(CH.sub.3).sub.2 H (CH.sub.2).sub.5 OH H     ##STR599##      303     ##STR600##      H CH.sub.2      CH(CH.sub.3).sub.2 H (CH.sub.2).sub.5 OH H     ##STR601##                304     ##STR602##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR603##      305     ##STR604##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR605##       306 H H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR606##      307     ##STR607##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR608##      308     ##STR609##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR610##      309     ##STR611##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR612##      310     ##STR613##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR614##      311     ##STR615##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR616##      312     ##STR617##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR618##      313     ##STR619##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR620##       314 H H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR621##      315     ##STR622##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR623##      316     ##STR624##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR625##      317     ##STR626##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR627##      318     ##STR628##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR629##      319     ##STR630##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR631##      320     ##STR632##      H      ##STR633##      H CH.sub.3 H OH H      ##STR634##      321     ##STR635##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR636##      322     ##STR637##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR638##      323     ##STR639##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR640##      324     ##STR641##      H      ##STR642##      H CH.sub.3 H OH H      ##STR643##      325     ##STR644##      H CH.sub. 2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR645##      326     ##STR646##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR647##      327     ##STR648##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR649##      328     ##STR650##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR651##      329     ##STR652##      H CH.sub.2 CH(CH.sub.3 ).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR653##      330     ##STR654##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR655##      ##STR656##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR657##      332     ##STR658##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR659##       333 H H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR660##      334     ##STR661##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR662##      335     ##STR663##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR664##      336     ##STR665##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR666##      337     ##STR667##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR668##      338     ##STR669##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR670##      339     ##STR671##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR672##      340     ##STR673##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR674##      341     ##STR675##      H      ##STR676##      H CH.sub.3 H OH H      ##STR677##      342     ##STR678##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H OH H      ##STR679##      343     ##STR680##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H OH H      ##STR681##      344     ##STR682##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR683##      345     ##STR684##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR685##      346     ##STR686##      H      ##STR687##      H CH.sub.3 H OH H      ##STR688##      347     ##STR689##      H      ##STR690##      H CH.sub.3 H OH H      ##STR691##      348     ##STR692##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR693##      349     ##STR694##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR695##      350     ##STR696##      H      ##STR697##      H CH.sub.3 H OH H      ##STR698##      351     ##STR699##      H      ##STR700##      H CH.sub.3 H OH H      ##STR701##      352     ##STR702##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR703##      353     ##STR704##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR705##      354     ##STR706##      H      ##STR707##      H CH.sub.3 H OH H      ##STR708##      355     ##STR709##      H      ##STR710##      H CH.sub.3 H OH H      ##STR711##      356     ##STR712##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH.sub.3 H OH H     ##STR713##      357     ##STR714##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR715##      358     ##STR716##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR717##       359 H H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR718##      360     ##STR719##      H CH.sub.2      CH(CH.sub.3).sub. 2 H CH(CH.sub.3).sub.2 H OH H     ##STR720##      361     ##STR721##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR722##      362     ##STR723##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR724##      363     ##STR725##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR726##      364     ##STR727##      H CH.sub.2      CH(CH.sub.3).sub.2 H  CH(CH.sub.3).sub.2 H OH H     ##STR728##      365     ##STR729##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR730##      366     ##STR731##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR732##      367     ##STR733##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR734##      368     ##STR735##      H  CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR736##      369     ##STR737##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR738##      370     ##STR739##      H      ##STR740##      H CH.sub.3 H OH H      ##STR741##      371     ##STR742##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH.sub.3 H OH H     ##STR743##      372     ##STR744##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR745##      373     ##STR746##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR747##      374     ##STR748##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR749##      375     ##STR750##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR751##       376     ##STR752##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR753##      377     ##STR754##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR755##      378     ##STR756##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR757##      379     ##STR758##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H  OH H     ##STR759##      380     ##STR760##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR761##      381     ##STR762##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR763##      382     ##STR764##      H      ##STR765##      H CH.sub.3 H OH H      ##STR766##      383     ##STR767##      H CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H OH H      ##STR768##      384     ##STR769##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR770##      385     ##STR771##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR772##      386     ##STR773##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR774##      387     ##STR775##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR776##      388     ##STR777##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR778##      389     ##STR779##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR780##      390     ##STR781##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR782##      391     ##STR783##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR784##      392     ##STR785##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR786##      393     ##STR787##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR788##      394     ##STR789##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR790##       395     ##STR791##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR792##      396     ##STR793##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR794##      397     ##STR795##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR796##      398     ##STR797##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR798##      399     ##STR799##      H      ##STR800##      H CH.sub.3 H OH H      ##STR801##      400     ##STR802##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH.sub.3 H OH H     ##STR803##      401     ##STR804##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR805##      402     ##STR806##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR807##      403     ##STR808##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR809##      404     ##STR810##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR811##      405     ##STR812##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR813##      406     ##STR814##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR815##      407     ##STR816##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR817##      408     ##STR818##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR819##      409     ##STR820##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.3 H OH H CH.sub.2 OH  410      ##STR821##      H      ##STR822##      H CH.sub.3 H OH H CH.sub.2 OH      411     ##STR823##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H CH.sub.2 OH     412      ##STR824##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H CH.sub.2 OH     413      ##STR825##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR826##      414     ##STR827##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR828##      415     ##STR829##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR830##      416     ##STR831##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR832##      417     ##STR833##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH.sub.3 H OH H     ##STR834##      418     ##STR835##      H      ##STR836##      H CH.sub.3 H OH H      ##STR837##      419     ##STR838##      H CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR839##      420     ##STR840##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR841##      421     ##STR842##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR843##      422     ##STR844##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR845##      423     ##STR846##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR847##       424 H H CH.sub.2 CH(CH.sub. 3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR848##      425     ##STR849##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR850##      426     ##STR851##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR852##      427     ##STR853##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR854##      428     ##STR855##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR856##      429     ##STR857##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR858##      430     ##STR859##      H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR860##      H OH H      ##STR861##      431     ##STR862##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR863##      432     ##STR864##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR865##      433     ##STR866##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR867##       434 H H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR868##      435     ##STR869##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR870##      436     ##STR871##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR872##      437     ##STR873##      H CH.sub. 2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR874##      438     ##STR875##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR876##      439     ##STR877##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR878##      440     ##STR879##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR880##      441     ##STR881##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR882##      442     ##STR883##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR884##      443     ##STR885##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR886##      444     ##STR887##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR888##      445     ##STR889##      H CH(CH.sub.3).sub.2 H CH.sub.2      CH(CH.sub.3 ).sub.2 H OH H     ##STR890##      446     ##STR891##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H OH H      ##STR892##      447     ##STR893##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR894##      448     ##STR895##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR896##

    TABLE 2      (n = 1) Compd.            No. R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5     R.sup.6 R.sup.7 R.sup.8 R.sup.9 R.sup.10 R.sup.11                   449      ##STR897##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.3     H OH H H      450     ##STR898##      H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR899##      H CH.sub.3 H OH H H      451     ##STR900##      H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR901##      H CH.sub.3 H OH H H      452     ##STR902##      H CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2     H OH H H      453     ##STR903##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H H      454     ##STR904##      H      ##STR905##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H H  455      ##STR906##      H CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2     CH.sub.2 CH.sub.3 H OH H H      456     ##STR907##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2     CH.sub.2 CH.sub.2 CH.sub.3 H OH H H      457     ##STR908##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2     CH.sub.2 CH.sub.2 CH.sub.3 H OH H H      458     ##STR909##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2     CH.sub.2 CH.sub.2 CH.sub.3 H OH H H      459     ##STR910##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR911##      H OH H H      460     ##STR912##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2     CH.sub.2 CH.sub.2 CH.sub.3 H OH H CH.sub.3      461     ##STR913##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2     CH.sub.2 CH.sub.2 CH.sub.3 H OH H CH.sub.3      462     ##STR914##      H      ##STR915##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H CH.sub.3      463     ##STR916##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.3     H OH H      ##STR917##      464     ##STR918##      H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR919##      H CH.sub.3 H OH H      ##STR920##      465     ##STR921##      H CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR922##      466     ##STR923##      H CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2     H OH H      ##STR924##      467     ##STR925##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR926##      468     ##STR927##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR928##      469     ##STR929##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR930##      470     ##STR931##      CH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H     CH(CH.sub.3).sub.2 H OH H      ##STR932##      471     ##STR933##      H CH.sub.2 CH(CH.sub.3).sub.2 CH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 H     CH(CH.sub.3).sub.2 H OH H      ##STR934##      472     ##STR935##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR936##       473 H H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H     CH(CH.sub.3).sub.2 H OH H      ##STR937##      474     ##STR938##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR939##      475     ##STR940##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR941##      476     ##STR942##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR943##      477     ##STR944##      H      ##STR945##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR946##      478     ##STR947##      H      ##STR948##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H     ##STR949##      479     ##STR950##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     CH(CH.sub.3).sub.2 H OH H      ##STR951##      480     ##STR952##      H CH.sub.3 H      ##STR953##      H CH(CH.sub.3).sub.2 H OH H      ##STR954##      481     ##STR955##      H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR956##      H CH(CH.sub.3).sub.2 H OH H      ##STR957##      482     ##STR958##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2     CH.sub.2      CH.sub.3 H OH H     ##STR959##      483     ##STR960##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2     CH.sub.2 CH.sub.2      CH.sub.3 H OH H     ##STR961##      484     ##STR962##      H      ##STR963##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 H     OH H      ##STR964##      485     ##STR965##      H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR966##      H CH.sub.2      CH(CH.sub.3).sub.2 H OH H     ##STR967##      486     ##STR968##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH.sub.3 H     ##STR969##      H OH H      ##STR970##      487     ##STR971##      H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H     ##STR972##      H OH H      ##STR973##      488     ##STR974##      H CH.sub.3 H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR975##      H OH H      ##STR976##      489     ##STR977##      H CH(CH.sub.3).sub.2 H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR978##      H OH H      ##STR979##      490     ##STR980##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2      CH(CH.sub.3).sub.2 H     ##STR981##      H OH H      ##STR982##      491     ##STR983##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub. 2      CH(CH.sub.3).sub.2 H     ##STR984##      H OH H      ##STR985##      492     ##STR986##      CH.sub.3 CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H      ##STR987##      H OH H      ##STR988##      493     ##STR989##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2     CH.sub.2 CH.sub.2      CH.sub.3 H OH H     ##STR990##      494     ##STR991##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2     CH.sub.2 CH.sub.2      CH.sub.3 H OH H     ##STR992##      495     ##STR993##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR994##      496     ##STR995##      H CH.sub.2 CH(CH.sub.3).sub.2 H CH.sub.2      CH(CH.sub.3).sub.2 H CH(CH.sub.3).sub.2 H OH H      ##STR996##

The compound (I) of the invention can be prepared using any of knownmethods. However, there are some preferable methods as will behereinafter explained in detail. ##STR997## (wherein R¹, R⁴, R⁵, R⁶, R⁷,R⁸, R¹¹ and R¹² are as defined above, and R¹⁵ is C₁ -C₉ alkyl group, Bocis tert-butoxy-carbonyl group).

The compound of the general formula (IV) above can be prepared bydissolving the cyclopropenone ketal of the general formula (II) above,readily available by known method, in ethereal solvent such astetrahydrofuran, diethyl ether or the like and adding strong base suchas n-butyllithium methyllithium, lithium diisopropylamide or the like inthe presence of an additive such as N,N,N',N'-tetramethylethylenediamine, hexamethylphosphoric triamide,1,3-dimethyl-2-imidazolidone or the like at -40° C. to -100° C. to givea lithio compound, which is followed by the addition oftert-butoxycarbonylaminoaldehyde derivative of formula (III). In thisreaction, the aldehyde of the general formula (III) above may be addedto the cerium salt of lithio compound which previously produced byadding a suspension of anhydrous cerium chloride in tetrahydrofuran,n-hexane or the like to said lithio compound.

Then, the compound (IV) is treated with a cation exchange resin such asAnberlist 15® or with a mineral acid such as dilute sulfuric acid inorder to selective deprotection of ketal so that the cyclopropenonederivative of the general formula (V) above can be obtained. Further,the compound (V) is allowed to react with a mineral acid such ashydrochloric acid, sulfuric acid or the like or an organic acid such asp-toluenesulfonic acid, methanesulfonic acid or the like, in a solventsuch as dichloromethane, chloroform, dioxane, ethyl acetate or the liketo isolate an amine salt (VI) as a stable compound.

Alternatively, the amine salt (VI) can be prepared in one step byreacting the compound of the general formula (IV) above with a mineralacid such as hydrogen chloride, hydrogen bromide, sulfuric acid or thelike or an organic acid such as p-toluenesulfonic acid, methanesulfonicacid or the like in a solvent such as dichloromethane, chloroform,dioxane, ethyl acetate or the like with simultaneous deprotection ofboth of the ketal and tert-butoxycarbonyl group.

Then, the cyclopropenone derivatives of the general formula (VIII) abovecan be prepared by activating the N-substituted amino acid derivative ofthe general formula (VII) above with a condensing agent such as isobutylchloroformate, diphenylphosphorylazide, carbonyldiimidazole, oxalylchloride, dicyclohexylcarbodiimide or the like, if necessary, in thepresence of an amine such as triethylamine, pyridine or the like,reacting it with the amine salt of the general formula (VI) obtainedabove and a base such as triethylamine, pyridine or the like.

Further, the amine salt of the general formula (IX) above can beobtained by treating with a mineral acid such as hydrogen chloride,hydrogen bromide, sulfuric acid, nitric acid or the like or an organicacid such as p-toluenesulfonic acid, methanesulfonic acid or the like todeprotect the tert-butoxycarbonyl group. Then, the compound of thegeneral formula (XI) above can be prepared by reacting the compound (IX)with the acyl chloride of the formula R¹² -CO-Cl in the presence of anamine such as triethylamine, pyridine or the like in an organic solventsuch as chloroform, methylene chloride, ethyl acetate, dimethylformamideor the like.

Similarly, the compound (XII) can be prepared by reacting the compound(IX) with the chloroformic acid derivative of the formula R¹² -O-CO-Cland the compound (XIII) by reacting the compound (IX) with theisocyanate of the formula R¹² --NCO, and the compound (XIV) by reactingthe compound (IX) with the sulfonyl chloride of the formula R¹² --SO₂--Cl. The compound (X) can be prepared by neutralizing the compound (IX)with an alkali such as lithium hydroxide, potassium hydroxide, sodiumhydroxide or the like or an anion exchange resin.

Further, the compound of the general formula (XV) above can be preparedby reacting the compound (X) -(XIV) with the acyl chloride of theformula R¹⁵ --CO--Cl in the presence of an amine such as triethylamine,pyridine or the like in a solvent such as dichloromethane, chloroform,1,2-dichloroethane or the like. The cyclopropenone derivative of thegeneral formula (XVI) above can be prepared by oxidizing the hydroxygroup of cyclopropenone derivative of formula (X) -(XIV) with aconventional oxidizing agent such as sulfur trioxide-pyridinecomplex-dimethyl sulfoxide, oxalyl chloride-dimethyl sulfoxide, aceticanhydride-dimethyl sulfoxide, N-chlorosuccinimide, chromiumchloride-pyridine complex or the like. ##STR998## wherein R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined above, and R¹⁶ is R¹² --CO--, R¹²--O--CO--, R¹² --NH--CO-- or R¹² --SO₂ -- (in which R¹² is as definedabove).

The cyclopropenone derivative of the general formula (XVIII) above canbe prepared by activating carboxyl group of the N-substituted amino acidderivative of formula (XVII) by adding a condensing agent such asisobutyl chloroformate, diphenylphosphoryl azide, carbonyl diimidazole,oxalyl chloride, dicyclohexyl carbodiimide or the like, if necessary, inthe presence of an amine such as triethylamine, pyridine or the like andthen reacting with amine of formula (XXII) above and a base such astriethylamine, pyridine or the like. ##STR999## wherein R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R¹¹ and Boc are as defined above.

The N-protected amino acid of the general formula (XIX) above isactivated with a condensing agent as described in the Production 1 andthen allowed to react a compound (IX) in the presence of a base to givea compound of formula (XX) above. The product (XX) can be converted intoan amine salt of formula (XXI) by treating with an acid selected fromthose described in the Production 1. Similarly, the amino group andhydroxyl group can be converted according to the process described inthe Production 1.

As will be seen from the results of Experiments below, the compounds (I)of the invention proved to possess a potent inhibitory activity againstthiol protease such as papain, cathepsin B, cathepsin H, cathepsin L,calpain or the like with excellent properties regarding oral absorbance,tissue transference and cell membrane permeability, indicating that theyare clinically useful in the treatment of various diseases such asmuscular dystrophy, amyotrophy, cardiac infarction, stroke, Alzheimer'sdisease, conscious disturbance and motor disturbance caused by braintrauma, multiple sclerosis, neuropathy of peripheral nerve, cataract,inflammation, allergy, fulminant hepatitis, osteoporosis, hypercalcemia,breast carcinoma, prostatic carcinoma, prostatomegaly or the like, andcan be used as cancer growth inhibitors, cancer metastasis preventiveagents or platelet-aggregation inhibitors.

When the compounds (I) of the present invention are clinically applied,they can be administered to subjects to be treated after formulatinginto appropriate forms containing, as an active ingredient, atherapeutically effective amount of compound (I) together with carrierstherefor. The appropriate ratio of the active ingredient to carriers mayvary from about 1% by weight to about 90% by weight. For example, thecompounds of the present invention may be orally administered afterformulating into an appropriate form such as granules, fine granules,powders, tablets, hard capsules, soft capsules, syrups, emulsions,suspensions, solutions or the like. They can be administeredintravenously, intramuscularly or subcutaneously in the form ofinjections. Furthermore, they may be formulated in the form ofsuppositories, or powders which are prepared for injections at the timeof use.

Formulations of the invention can be prepared using any of known methodsin the art employing conventional carriers including organic orinorganic, solid or liquid, pharmaceutical carriers or diluents suitablefor oral, enteral or parenteral administration. Examples of excipientusable for preparing solid formulations are lactose, sucrose, starch,talc, cellulose, dextrin, kaolin, calcium carbonate and the like. Liquidformulations for oral administration such as emulsion, syrups,suspensions, solutions or the like include generally usable inertdiluents such as water, vegetable oils or the like. These formulationsmay further include adjuncts such as humectants, suspension aids,edulcorants, aromatics, tinctions or preservatives in addition to theinert diluents. The compound (I) can be formulated into solutions whichare filled in absorbable carriers such as hard or soft gelatin capsules.Examples of solvents and suspending agents usable for preparingpharmaceutical formulations such as injections, suppositories or thelike are water, propylene glycol, polyethylene glycol, benzyl alcohol,ethyl oleate, lecithin and the like. Examples of the base usable forsuppositories are cacao butter, emulsified cacao butter, lauric acid,Wittep sol and the like.

The dose of compound (I) may vary depending on various factors such asage, conditions or symptoms of the patient to be treated and the like.Appropriate daily dosage of the compound (I) of the present invention onoral administration to adult is generally about 0.01-1000 mg though, itis preferable to adjust appropriately for each case according to theconditions as mentioned above. The daily dosage of the compound (I) maybe administered once or in two or three divisions at appropriateintervals or intermittently.

Additionally, when the compound (I) is administered in the form ofinjections, one dosage of 0.001-100 mg of said compound can bepreferably administered to adult continuously or intermittently.

The following Examples further describe the present invention in moredetail, but these are illustrative only and are not intended to limitthe scope of the invention.

REFERENCE EXAMPLE 1 Preparation of2-{(2S)-2-tert-butoxycarbonylamino-1-hydroxy-3-methylbutyl}-3-phenylcyclopropenone2, 2-dimethyl-1,3-propanediyl ketal

To a solution of 3.51 g of 2-phenylcyclopropenone 2,2-dimethyl-l,3-propanediyl ketal in 30 ml of tetrahydrofuran was added3.8 g of N,N,N',N'-tetramethylethyldiamine. To the reaction solutionchilled at -78° C. was added a 1.55 mol/l solution of n-butyllithium in10.5 ml of hexane, and the mixture was stirred for 20 minutes. Then, 30ml of a tetrahydrofuran suspension of anhydrous cerium chloride preparedby drying 8.0 g of cerium chloride heptahydrate at 140° C./l mm Hg for 2hours was added to the mixture, which was stirred for 20 minutes. Asolution of 1.82 g of N-tert-butoxycarbonyl-L-valinal in 20 ml oftetrahydrofuran was added, and the resultant mixture was stirred at -78°C. for 2 hours. A solution of 1 ml of water in 5 ml of tetrahydrofuranwas added to the reaction mixture, which was allowed to warm at roomtemperature and filtered through celite. The celite was washed well withethyl acetate, and the filtrate was dried over sodium sulfate, filtered,concentrated and chromatographed on a column of silica gel, eluting withhexane containing 20% ethyl acetate as a developing solvent to give 2.71g of the titled product.

Yield: 72%

IR(KBr, cm⁻¹): 3430, 2960, 1855, 1800, 1710, 1690

NMR(CD₃ OD, δ): 0.95-1.60(m, 12H), 1.38(s, 3H), 1.42(s, 6H),1.95-2.15(m, 1H), 3.60-3.75(m, 1H), 3.75-3.95(m, 4H), 5.0-5.10(m, 1H),6.03(d, J=10 Hz, 0.33H), 6.23(d, J=10 Hz, 0.67H), 7.40-7.65(m, 3H),7.70-7.90(m, 2H)

REFERENCE EXAMPLE 2

Preparation of2-{(2S)-2-amino-1-hydroxy-3-methylbutyl}-3-phenylcyclopropenonehydrochloride

To 8 ml of a dioxane solution of 3.12 g of2-{(2S)-2-tert-butoxycarbonylamino-1-hydroxy-3-methylbutyl}-3-phenylcyclopropenone2,2-dimethyl-l,3-propanediyl ketal obtained in Reference Example 1 wereadded 0.2 ml of water and 24 ml of a dioxane solution of 4N hydrogenchloride, and the mixture was stirred for 20 minutes. The resultingcrystals were filtered and washed with dioxane to give 1.87 g of thetitled product.

Yield: 94%

IR(KBr, cm⁻¹): 3200, 1855, 1618

NMR(CD₃ OD, δ): 1.21(t, J=7 Hz, 4.5H), 1.24(t, J=7 Hz, 1.5H), 2.0-2.2(m,0.25H), 2.2-2.4(m, 0.75H), 3.38(t, J=6 Hz, 0.25H), 3.45(t, J=6 Hz,0.75H), 5.21(d, J=6 Hz, 0.75H), 5.45(d, J=6 Hz, 0.25H), 7.60-7.80(m,3H), 8.10-8.20(m, 2H)

EXAMPLE 1 Preparation of2-[(1S,2S)-2-{(s)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino}-1-hydroxy-3-methylbuthyl]-3-phenylcyclopropenone(Comp. No. 77 in Table 1)

To a solution of 2.46 g of N-cyclohexylmethoxycarbonyl-(S)-leucine in 40ml of methylene chloride chilled at -5° C. were added 0.92 g oftriethylamine and 1.15 g of isobutyl chloroformate, and the resultantmixture was stirred for 15 minutes. Further, 1.87 g of2-{(2S)-2-amino-1-hydroxy-3-methylbuty}-3-phenylcyclopropenonehydrochloride prepared in Reference Example 2 and 0.97 g oftriethylamine were added, and one hour later 10 ml of 0.5N hydrochloricacid was added. The resultant mixture was shaken with methylenechloride, and the organic layer was washed with water, saturated aqueoussodium bicarbonate and saturated brine in that order, dried overmagnesium sulfate and filtered. The filtrate was concentrated andchromatographed on a column of silica gel, eluting with hexane:ethylacetate (1:1) as developing solvent, and the product was recrystallizedfrom diethyl ether to give 1.86 g of the titled product.

Yield: 55%

mp: 85-89° C.

IR(KBr, cm⁻¹): 3330, 1858, 1695, 1658, 1625

NMR(CDCl₃, δ): 0.65-1.80(m, 26H), 2.25-2.45(m, 1H), 3.55-3.85(m, 3H),4.0-4.15(m, 1H), 5.12(d, J=4 Hz, 1H), 5.30-5.45(m, 1H), 7.40-7.65(m,4H), 7.95-8.05(m, 2H)

EXAMPLE 2 Preparation of 2-[(1R,2S)-2-{(S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(Comp. No. 77 in Table 1)

The titled isomer was obtained as a product of the chromatography on acolumn of silica gel in Example 1.

Yield: 18%

mp: 148-149° C.

IR(KBr, cm⁻¹): 1 3350, 3260, 1860, 1825, 1715, 1653, 1625

NMR(CDCl₃, δ): 0.60-1.80(m, 26H), 2.05-2.25(m, 1H), 3.60-3.85(m, 2H),4.05-4.20(m, 2H), 5.15(d, J=3 Hz, 1H), 5.20-5.40(m, 1H), 7.05(d., J=8Hz, 1H), 7.45-7.60(m, 3H), 7.95-8.05(m, 2H)

EXAMPLE 3 Preparation of2-[(1R,2S)-1-acetoxy-2-{(S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino}-3-methylbutyl]-3-phenylcyclopropenone(Comp. No. 78 in Table 1)

To 5 ml of a methylene chloride solution of 149 mg of2-[(1R,2S)-2-{(S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenyl-cyclopropenoneobtained in Example 2 were added 81 mg of acetyl chloride and 102 mg oftriethylamine. The resultant mixture was stirred at room temperature for3 hours, mixed with diluted hydrochloric acid and shaken with methylenechloride. The organic layer was washed with water, saturated aqueoussodium bicarbonate and saturated brine in that order, dried overmagnesium sulfate and filtered. The filtrate was concentrated andchromatographed on a column of silica gel, eluting with hexane:ethylacetate (1:1) to give 73 mg of the titled product.

Yield: 45%

IR(KBr, cm⁻¹): 3350, 3280, 1868, 1758, 1720, 1704, 1670, 1635

NMR(CDCl₃, δ): 0.79(d, J=7.0 Hz, 3H), 0.81(d, J=6.3 Hz, 3H),0.70-0.95(m, 2H), 1.02(d, J=6.6 Hz, 3H), 1.15(d, J=6.6 Hz, 3H),1.05-1.35(m, 4H), 1.35-1.85(m, 8H), 2.03(m, 1H), 2.20(s, 3H), 3.75(s,2H), 4.10(m, 1H), 4.31(m, 1H), 5.06(d, J=8.0 Hz, 1H), 6.12(d, J=4.2 Hz,1H), 6.52(d, J=8.1 Hz, 1H), 7.45-7.65(m, 3H), 7.84(d, J=7.1 Hz, 2H)

The compounds in the following Examples 4-120 were prepared by the samemanner as in Reference Examples 1-2 and Examples 1, 2 and 3.physicochemical properties of each compound are shown below.

EXAMPLE 4 Preparation of2-[(2S)-2-((S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]cyclopropenone (compd. No. 4 in Table 1)

IR(KBr, cm⁻¹): 3310, 1825, 1690, 1650

NMR(CDCl₃, δ): 0.80-1.80(m, 26H), 1.90-2.35(m, 2H), 3.60-4.25(m, 4H),4.87-5.05(m, 1H), 5.05-5.45(m, 1H), 6.85-7.03(m, 0.3H), 7.35-7.52(m,0.7H), 8.54(s, 0.7H), 8.62(s, 0.3H)

EXAMPLE 5 Preparation of2-[(2S)-2-((S)-2-benzyloxycarbonylamino-4-methylvalerylamino)-1-hydroxy-4-methylpentyl]cyclopropenone(compd. No. 10 in Table 1)

IR(KBr, cm⁻¹): 3320, 1825, 1697, 1652

NMR(CDCl₃, δ): 0.90-1.05(m, 12H), 1.40-1.80(m, 6H), 4.05-4.32(m, 2H),4.68-4.87(m, 1H), 5.09(s, 2H), 4.90-5.60(m, 2H), 6.85-7.10(m, 1H),7.34(s, 5H), 8.43(s, 0.95H), 8.62(s, 0.05H)

EXAMPLE 6 Preparation of2-[(2S)-2-((S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino)-1-hydroxyhexyl]cyclopropenone(compd. No. 15 in Table 1)

IR(KBr, cm⁻¹): 3340, 1830, 1690, 1650

NMR(CDCl₃, δ): 0.80-1.05(m, 11H), 1.10-1.88(m, 18H), 2.24(s, 1H),3.73-3.95(m, 2H), 4.05-4.30(m, 2H), 4.80-4.93(m, 1H), 5.20-5.35(m,0.2H), 5.35-5.55(m, 0.8H), 5.55-5.75(m, 0.8H), 6.95-7.05(m, 0.2H),8.57(s, 0.8 H), 8.68(s, 0.2H)

EXAMPLE 7 Preparation of2-[(2S)-2-((S)-2-benzyloxycarbonylamino-4-methylvalerylamino)-1-hydroxyhexyl]cyclopropenone(compd. No. 16 in Table 1)

IR(KBr, cm⁻¹): 3320, 1828, 1690, 1645

NMR(CDCl₃, δ): 0.75-1.0(m, 9H), 1.15-1.85(m, 9H), 2.25(s, 1 H),3.98-4.27(m, 2H), 4.68-4.87(m, 1H), 5.07(s, 2H), 5.45-5.80(m, 1.8H),6.95-7.05(m, 0.2H), 7.32(s, 5H), 8.43(s, 0.8 H), 8.57(s, 0.2H)

EXAMPLE 8 Preparation of2-[(2S)-1-acetoxy-2-((S)-2-benzyloxycarbonylamino-4-methylvalerylamino)hexyl]cyclopropenone(compd. No. 20 in Table 1)

IR(neat, cm⁻¹): 3320, 1845, 1755, 1725, 1710, 1668

NMR(CDCl₃, δ): 0.80-1.0(m, 9H), 1.20-1.75(m, 9H), 2.15(s, 0.45H),2.20(s, 2.55H), 4.08-4.23(m, 1H), 4.35-4.50(m, 1H), 5.20(s, 2H), 5.18(d,J=7 Hz, 0.85H), 5.22(d, J=7 Hz, 0.15H), 5.70(d, J=4 Hz, 0.85H), 6.78(d,J=4 Hz, 0.15H), 6.43(d, J=8 Hz, 0.15H), 6.46(d, J=8 Hz, 0.85H), 7.35(s,5H), 8.49(s, 0.85H), 8.52(s, 0.15H)

EXAMPLE 9 Preparation of2-[(2S)-2-((S)-2-benzyloxycarbonylamino-4-methylvalerylamino)-1-hydroxy-3-phenylpropyl]cyclopropenone(compd. No. 26 in Table 1)

IR(KBr, cm⁻¹): 3330, 1830, 1700, 1655

NMR(CDCl₃, δ): 0.65-0.95(m, 6H), 1.10-1.65(m, 3H), 1.93(s, 1H),2.75-3.25(m, 2H), 3.90-4.55(m, 2H), 4.60-4.83(m, 1H), 5.05(s, 2H),5.15-5.85(m, 2H), 7.05-7.45(m, 10H), 8.39(s, 0.8 H), 8.53(s, 0.2H)

EXAMPLE 10 preparation of2-[(2S)-2-((S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino)-1-hydroxyhexyl]-3-methylcyclopropenone(compd. No. 34 in Table 1)

IR(KBr, cm⁻¹): 3320, 1845, 1690, 1653, 1630 NMR(CDCl₃, δ): 0.85-1.10(m,11H), 1.10-1.95(m, 18H), 2.33(s, 3H), 2.49(s, 1H), 3.75-3.97(m, 2H),3.97-4.28(m, 2H), 4.73-4.90(m, 1H), 5.20-5.85(m, 1.6H), 7.10-7.50(m,0.4H)

EXAMPLE 11 Preparation of2-[(2S)-2-((S)-2-benzyloxycarbonylamino-4-methylvalerylamino)-1-hydroxy-4-methylpentyl]-3-ethylcyclopropenone(compd. No. 40 in Table 1

IR(neat, cm⁻¹): 3330, 1845, 1700, 1658, 1625

NMR(CDCl₃, δ): 0.85-1.05(m, 12H), 1.30(q, J=7 Hz, 3H), 1.40-1.75(m, 6H),1.83(s, 1H), 2.58-2.78(m, 2H), 3.80-4.30(m, 2H), 4.65-4.85(m, 1H),4.90-5.03(m, 0.5H), 5.09(m, 2H), 5.37-5.65(m, 1.5H), 5.70-5.85(m, 0.5H),7.05-7.25(m, 0.5H), 7.34(s, 5H)

EXAMPLE 12 Preparation of2-[(2S)-2-((S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino)-1-hydroxyhexyl]-3-isopentylcyclopropenone(compd. No. 44 Table 1)

IR(KBr, cm⁻¹): 3310, 1838, 1720, 1698, 1652, 1620

NMR(CDCl₃, δ): 0.85-1.10(m, 17H), 1.10-1.85(m, 21H), 2.45-2.55(m, 1H),2.55-2.70(m, 2H), 3.73-3.93(m, 2H), 3.93-4.25(m, 2H), 4.70-4.85(m, 1H),5.25-5.85(m, 1.6H), 7.30-7.45(m, 0.4H)

EXAMPLE 13 Preparation of2-[(1S,2S)-2-((S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino)-1-hydroxyhexyl]-3-((Z)-1-hexenyl)cyclopropenone(compd. No. 55 in Table 1)

mp: 138°-140° C.

IR(KBr, cm⁻¹): 3290, 1838, 1711, 1655, 1630

NMR(CDCl₃, δ): 0.83-1.08(m, 14H), 1.10-2.05(m, 22H), 2.56(m, 2H),3.85(s, 2H), 4.02(m, 1H), 4.15(m, 1H), 4.82(m, 1H), 5.22-5.48(m, 2H),6.26(d, J=10 Hz, 1H), 6.48(m, 1H), 7.08(m, 1H)

EXAMPLE 14 Preparation of2-[(1S,2S)-2-((S)-2-benzyloxycarbonylamino-4-methylvalerylamino)-1-hydroxyhexyl]-3-((Z)-1-hexenyl)cyclopropenone(compd. No. 56 in Table 1)

mp: 87°-94° C.

IR(KBr, cm⁻¹): 3300, 1836, 1689, 1645

NMR(CDCl₃, δ): 0.80-1.03(m, 12H), 1.22-1.80(m, 13H), 2.56(m, 2H),4.01(m, 1H), 4.17(m, 1H), 4.77(m, 1H), 5.08(s, 2H), 5.19(m, 1H), 5.45(m,1H), 6.24(d, J=9.9 Hz, 1H), 6.46(m, 1H), 7.04(d, J=7.7 Hz, 1H), 7.33(s,5H)

EXAMPLE 15 Preparation of2-[(1S,2S)-2-((S)-2-benzyloxycarbonylamino-4-methylvalerylamino)-1-hydroxyhexyl]-3-((E)-1-hexenyl)cyclopropenone(compd. No. 58 in Table 1)

mp: 116° C.

IR(KBr, cm⁻¹): 3308, 1842, 1698, 1655

NMR(CDCl₃, δ): 0.85-1.0(m, 12H), 1.15-1.90(m, 13H), 2.27(dt, J=6.8 Hz,6.5 Hz, 2H), 3.97(m, 1H), 4.17(m, 1H), 4.75(m, 1H), 5.08(s, 2H), 5.57(d,J=6.5 Hz, 1H), 6.24(d, J=16 Hz, 1H), 6.90(dt, J=16 Hz, 6.8 Hz, 1H),7.10(d, ^(J=) 6.8 Hz, 1H), 7.32(s, 5H)

EXAMPLE 16 preparation of2-[(1S,2S)-2-((S)-2-benzyloxycarbonylaminopropionylamino)-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 68 in Table

mp: 156°-158° C.

IR(KBr, cm⁻¹): 3290, 1850, 1690, 1643, 1618

NMR(CDCl₃, δ): 0.98(d, J=5.9 Hz, 3H), 1.07(d, J=6.6 Hz, 3H), 1.19(d,J=7.0 Hz, 3H), 2.36(m, 1H), 3.61(m, 1H), 4.18(m, 1H), 4.90-5.15(m, 3H),5.47(m, 1H), 7.31(s, 5H), 7.25-7.65(m, 5H), 7.95(d, J=7.4 Hz, 2H)

EXAMPLE 17 Preparation of2-[(2S)-2-((S)-2-benzyloxycarbonylaminopropionylamino)-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 68 in Table 1)

IR(KBr, cm⁻¹): 3280, 1852, 1696, 1642, 1618

NMR(CDCl₃, δ): 0.85-1.30(m, 9H), 2.11(m, 0.4H), 2.34(m, 0.6H), 3.64(m,0.6H), 4.02-4.28(m, 1.4H), 4.85-5.20(m, 3H), 5.49(m, 0.4H), 5.62(m,0.6H), 6.99(d, J=7.7 Hz, 0.6H), 7.15-7.38(m, 5.4H), 7.15-7.65(m, 4H),7.88-8.05(m, 2H)

EXAMPLE 18 Preparation of 2-[(1S,2S)-2-((S)-2-benzyloxycarbonylamino-3-methylbutyrylamino)-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 70 in Table 1)

mp: 157°-158° C.

IR(KBr, cm⁻¹): 3310, 1850, 1697 1643, 1618

NMR(CDCl₃, δ): 0.74(d, J=6.8 Hz, 3H), 0.85(d, J=6.7 Hz, 3H), 0.98(d,J=6.5 Hz, 3H), 1.08(d, J=6.6 Hz, 3H), 2.04(m, 1H), 2.36(m, 1H), 3.69(m,1H), 4.01(m, 1H), 4.90-5.10(m, 3H), 5.47(d, J=8.2 Hz, 1H), 6.15(d, J=8.2Hz, 1H), 7.30(s, 5H), 7.40-7.60(m, 4H), 7.93-8.0(m, 2H)

EXAMPLE 19 Preparation of 2-[(1R,2S)-2-((S)-2-benzyloxycarbonylamino-3-methylbutyrylamino)-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 70 in Table 1)

mp: 63°-71° C.

IR(KBr, cm⁻¹): 3310, 1860, 1700, 1660, 1630

NMR(CDCl₃, δ): 0.79(d, J=6.8 Hz, 3H), 0.80(d, J=6.9 Hz, 3H), 1.05(d,J=6.7 Hz, 3H), 1.13(d, J=6.6 Hz, 3H), 1.98(m, 1H), 2.14(m, 1H),3.90-4.15(m, 2H), 4.92(d, J=12 Hz, 1H), 5.03(d, J=12 Hz, 1H), 5.13(m,1H), 5.42(d, J=7.0 Hz, 1H), 6.96(d, J=7.2 Hz, 1H), 7.30(s, 5H),7.40-7.63(m, 4H), 7.97(d, J=7.0 Hz, 2H)

EXAMPLE 20 Preparation of 2-[(1S,2S)-1-hydroxy-2-((S)-2-isobutoxycarbonylamino-4-methylvalerylamino)-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 72 in Table 1)

mp: 145°-146° C.

IR(KBr, cm⁻¹): 3320, 1848, 1692, 1644, 1620

NMR(CDCl₃, δ): 0.77(d, J=4.3 Hz, 6H), 0.87(d, J=6.7 Hz, 6H), 1.01(d,J=6.5 Hz, 3H), 1.09(d, J=6.5 Hz, 3H), 1.29(m, 2H), 1.52(m, 1H), 1.84(m,1H), 2.39(m, 1H), 3.60-3.87(m, 3H), 4.10(m, 1H), 5.12(d, J=3.5 Hz, 1H),5.29(m, 1H), 6.20(s, 1H), 7.38-7.60(m, 4H), 7.98(d, J=6.9 Hz, 2H)

EXAMPLE 21 Preparation of 2-[(1R,2S)-1-hydroxy-2-((S)-2-isobutoxycarbonylamino-4-methylvalerylamino)-3-methylbutyl]-3-phenylcyclopropenone(compd- No. 72 in Table 1)

mp: 173°-174° C.

IR(KBr, cm⁻¹): 3400, 3260, 1863, 1828, 1722, 1655, 1626

NMR(CDCl₃, δ): 0.71(d, J=4.1 Hz, 6H), 0.84(d, J=6.6 Hz, 6H), 1.08(d,J=6.5 Hz, 3H), 1.14(d, J=6.6 Hz, 3H), 1.30-1.60(m, 2H), 1.60-1.90(m,2H), 2.13(m, 1H), 3.55-3.90(m, 2H), 3.98-4.18(m, 2H), 5.03-5.18(m, 3H),6.79(m, 1H), 7.40-7.63(m, 3H), 7.99(d, J=7.8 Hz, 2H)

EXAMPLE 22 Preparation of 2-[(1S,2S)-2-((S)-2-tert-butoxycarbonylamino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 73 in Table 1)

mp: 158°-161° C.

IR(KBr, cm⁻¹): 3330, 1858, 1685, 1655, 1625

NMR(CDCl₃, δ): 0.75(d, J=6.4 Hz, 6H), 1.02(d, J=6.7 Hz, 3H), 1.09(d,J=6.6 Hz, 3H), 1.17-1.60(m, 3H), 1.39(s, 9H), 2.39(m, 1H), 3.65(m, 1H),4.04(m, 1H), 5.02-5.18(m, 2H), 6.25(m, 1H), 7.33(m, 1H), 7.45-7.60(m,3H), 7.95-8.05(m, 2H)

EXAMPLE 23 Preparation of 2-[(1R,2S)-2-((S)-2-tert-butoxycarbonylamino-4-methylvalerylamino)-1-hydroxy3-methylbutyl]-3-phenylcyclopropenone(compd. No. 73 in Table 1)

mp: 182°-183° C.

IR(KBr, cm⁻¹): 1 3380, 3260, 1860, 1825, 1708, 1655, 1625

NMR(CDCl₃, δ): 0.68(d, J=5.6 Hz, 6H), 1.08(d, J=6.6 Hz, 3H), 1.11(d,J=6.7 Hz, 3H), 1.25-1.55(m, 3H), 1.38(s, 9H), 2.13(m, 1H), 3.98-4.13(m,2H), 5.04(d, J=5.9 Hz, 1H), 5.13(dd, J=6.4 Hz, 3.0 Hz, 1H), 5.35(d,J=6.4 Hz, 1H), 8.95(d, J=7.0 Hz, 1H), 7.45-7.65(m, 3H), 7.98-8.07(m, 2H)

EXAMPLE 24 Preparation of 2-[(1S,2S)-2-{N-((S)-2-cyclohexylcarbonylamino-4-methylvaleryl)-N-methylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 80 in Table 1)

IR(KBr, cm⁻¹): 3416, 1856, 1716, 1640

NMR(CDCl₃, δ): 0.86(d, J=7.1 Hz, 3H), 0.92(d, J=7.1 Hz, 3H), 0.97(d,J=6.5 Hz, 3H), 1.10(d, J=6.6 Hz, 3H), 0.65-1.80(m, 14H), 2.64(m, 1H),3.22(s, 3H), 3.05-3.40(m, 2H), 3.53(dd, J=11 Hz, 7.0 Hz, 1H), 4.45(m,1H), 4.87(d, J=8.7 Hz, 1H), 5.10(dd, J=9.1 Hz, 4.3 Hz, 1H), 6.80(m, 1H),7.35-7.60(m, 3H), 7.93(d, J=7.2 Hz, 2H)

EXAMPLE 25 Preparation of 2-[(1S,2S)-2-((S)-2-benzyloxycarbonylamino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 83 in Table 1)

mp: 84°-94° C.

IR(KBr, cm⁻¹): 3320, 1855, 1700, 1655, 1625

NMR(CDCl₃, δ): 0.60-0.85(m, 6H), 0.97(d, J=6 Hz, 3H), 1.07(d, J=6 Hz,3H), 1.20-1.60(m, 3H), 1.85-2.25(m, 1H), 2.25-2.45(m, 1H), 3.55-3.70(m,1H), 4.0-4.10(m, 1H), 4.85-5.15(m, 3H), 5.53(d, J=8 Hz, 1H), 7.29(s,5H), 7.40-7.60(m, 4H), 7.90-8.05(m, 2H)

EXAMPLE 26 Preparation of2-[(2S)-2-((S)-2-benzyloxycarbonylamino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 83 in Table 1)

IR(KBr, cm⁻¹): 3300, 1855, 1700, 1655, 1625

NMR(CDCl₃, δ): 0.60-1.55(m, 15H), 2.05-2.25(m, 1.6H), 2.25-2.45(m,0.4H), 3.55-3.70(m, 0.4H), 3.95-4.25(m, 1.6H), 4.85-5.20(m, 3H), 5.53(d,J=8 Hz, 0.6H), 5.62(d, J=8 Hz, 0.4H), 7.08(d, J=8 Hz, 0.6H), 7.50(s,5H), 7.40-7.65(m, 3.4H), 7.90-8.10(m, 2H)

EXAMPLE 27 Preparation of 2-[(1S,2S)-2-{(S)-2-(N-benzyloxycarbonyl-N-methylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 85 in Table 1)

mp: 117° C.

IR(KBr, cm⁻¹): 3335, 3298, 1858, 1699, 1672, 1628

NMR(CDCl₃, δ): 0.70-0.90(m, 6H), 0.96(d, J=6.6 Hz, 3H), 1.03(d, J=6.6Hz, 3H), 1.25-1.65(m, 3H), 2.35(m, 1H), 2.57(s, 3H), 3.62(m, 1H),4.64(m, 1H), 5.07(d, J=4.9 Hz, 1H), 5.15(s, 2H), 7.04(d, J=7.5 Hz, 1H),7.36(s, 5H), 7.38-7.58(m, 3H), 7.94(d, J=6.5 Hz, 2H)

EXAMPLE 28 Preparation of 2-[(1R,2S)-2-{(S)-2-(N-benzyloxycarbonyl-N-methylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 85 in Table 1)

mp: 112° C.

IR(KBr, cm⁻¹): 3320, 3283, 1863, 1703, 1661, 1632

NMR(CDCl₃, δ): 0.70(d, J=8.4 Hz, 3H), 0.73(d, J=6.7 Hz, 3H), 0.96(d,J=5.1 Hz, 3H), 1.09(d, J=6.4 Hz, 3H), 1.28(m, 1H), 1.40-1.70(m, 2H),2.05(m, 1H), 2.80(s, 3H), 3.94(m, 1H), 4.48(t, J=7.3 Hz, 1H),4.94-5.20(m, 3H), 6.65(m, 1H), 7.33(s, 5H), 7.38-7.62(m, 3H), 7.98(d,J=6.4 Hz, 2H)

EXAMPLE 29 Preparation of 2-[(1s,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(2-pyridylmethoxycarbonylamino)valerylamino}butyl]-3-phenylcyclopropenonehydrochloride (compd. No. 97 in Table 1)

mp: 158°-160° C.(dec.)

IR(KBr, cm⁻¹): 3279, 1854, 1738, 1676, 1630, 1615

NMR(CD₃ OD, δ): 0.52(d, J=6.6 Hz, 3H), 0.64(d, J=6.5 Hz, 3H), 0.90(d,J=6.7 Hz, 3H), 0.95-1.33(m, 2H), 1.07(d, J=6.7 Hz, 3H), 1.46(m, 1H),2.05(m, 1H), 3.97-4.16(m, 2H), 5.21(d, J=2.4 Hz, 1H), 5.28(d, J=15 Hz,1H), 5.43(d, J=15 Hz, 1H), 7.50-7.70(m, 3H), 7.97-8.15(m, 4H), 8.61(td,J=8.0 Hz, 1.5 Hz, 1H), 8.81(d, J=5.2 Hz, 1H)

EXAMPLE 30 Preparation of 2-[(1R,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(2-pyridylmethoxycarbonylamino)valerylamino}butyl]-3-phenylcyclopropenone(compd. No. 97 in Table 1)

mp: 52°-59° C.

IR(KBr, cm⁻¹): 3300, 1858, 1715, 1660, 1630

NMR(CDCl₃, δ): 0.71(d, J=7.4 Hz, 6H), 1.03(d, J=6.3 Hz, 3H), 1.11(d,J=6.4 Hz, 3H), 1.38-1.65(m, 3H), 2.42(m, 1H), 4.09(m, 1H), 4.20(m, 1H),4.95-5.28(m, 3H), 5.43(m, 1H), 5.78(d, J=7.7 Hz, 1H), 7.15-7.38(m, 3H),7.38-7.62(m, 3H), 7.62-7.78(m, 1H), 7.97(d, J=7.0 Hz, 2H), 8.54(s, 1H)

EXAMPLE 31 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(4-pyridylmethoxycarbonylamino)valerylamino}butyl]-3-phenylcyclopropenonehydrochloride (compd. No. 99 in Table 1)

mp: 122°-129° C.(dec.)

IR(KBr, cm⁻¹): 3260, 1858, 1720, 1650, 1640, 1615

NMR(CD₃ OD, δ): 0.53(d, J=6.6 Hz, 3H), 0.64(d, J=6.5 Hz, 3H), 0.91(d,J=6.7 Hz, 3H), 1.08(d, J=6.7 Hz, 3H), 0.79-1.20(m, 2H), 1.53(m, 1H),2.10(m, 1H), 4.0-4.18(m, 2H), 5.21(s, 1H), 5.24(d, J=20 Hz, 1H), 5.30(d,J=20 Hz, 1H), 7.53-7.70(m, 3H), 7.95-8.15(m, 4H), 8.82(d, J=6.8 Hz, 2H)

EXAMPLE 32 Preparation of 2-[(1R,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(4-pyridylmethoxycarbonylamino)valerylamino}butyl]-3-phenylcyclopropenonehydrochloride (compd. No. 99 in Table 1)

mp: 116°-134° C.(dec.)

IR(KBr, cm⁻¹): 3260, 1857, 1720, 1660, 1635, 1620

NMR(CD₃ OD, δ): 0.82(d, J=6.3 Hz, 6H), 0.84(d, J=6.4 Hz, 6H), 1.53(m,2H), 1.73(m, 1H), 2.13(m, 1H), 4.0-4.25(m, 2H), 5.05(d, J=7.0 Hz, 1H),5.32(d, J=17 Hz, 1H), 5.43(d, J=17 Hz, 1H), 7.53-7.70(m, 3H),7.90-8.10(m, 4H), 8.82(d, J=6.SHz, 2H)

EXAMPLE 33 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-((S)-4-methyl-2-phenoxycarbonylamino)valerylamino]-3-phenylcyclopropenone(compd. No. 102 in Table 1)

mp: 105°-115° C.

IR(KBr, cm⁻¹): 3304, 1856, 1717, 1657, 1626

NMR(CDCl₃, δ): 0.75(d, J=6.1 Hz, 3H), 0.77(d, J=6.3 Hz, 3H), 1.0(d,J=6.6 Hz, 3H), 1.04(d, J=6.7 Hz, 3H), 1.35(m, 2H), 1.56(m, 1H), 2.33(m,1H), 3.70(m, 1H), 4.17(m, 1H), 5.09(dd, J=8.3 Hz, 4.1 Hz, 1H), 6.17(d,J=9.1 Hz, 1H), 6.21(d, J=8.3 Hz, 1H), 7.02(d, J=7.7 Hz, 2H), 7.16(t,J=7.2 Hz, 1H), 7.30(t, J=7.4 Hz, 2H), 7.42-7.62(m, 3H), 7.70(d, J=7.9Hz, 1H), 7.94(d, J=6.7 Hz, 2H)

EXAMPLE 34 Preparation of 2-[(1S,2S)-2-((S)-2-amino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenonehydrochloride (compd. No. 105 in Table 1)

mp: 147°-153° C.(dec.)

IR(KBr, cm⁻¹): 3260, 1858, 1675, 1616

NMR(CD₃ OD, δ): 0.47(d, J=6.5 Hz, 3H), 0.71(d, J=6.5 Hz, 3H), 1.02(d,J=6.7 Hz, 3H), 1.12(d, J=6.7 Hz, 3H), 1.20(m, 2H), 1.42(m, 1H), 2.10(m,1H), 3.81(dd, J=8.9 Hz, 6.1 Hz, 1H), 4.11(dd, J=9.7 Hz, 2.2 Hz, 1H),5.23(d, J=2.2 Hz, 1H), 7.55-7.70(m, 3H), 8.03-8.13(m, 2H)

EXAMPLE 35 Preparation of 2-[(1R,2S)-2-((S)-2-amino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenonehydrochloride (compd. No. 105 in Table 1)

mp: 133°-136° C.

IR(KBr, cm⁻¹): 3260, 1860, 1675, 1620

NMR(CD₃ OD, δ): 0.82(d, J=5.6 Hz, 3H), 0.85(d, J=5.7 Hz, 3H), 1.04(d,J=6.7 Hz, 3H), 1.10(d, J=6.8 Hz, 3H), 1.58-1.80(m, 3H), 2.16(m, 1H),3.84(m, 1H), 4.03(t, J=7.0 Hz, 1H), 5.18(d, J=6.6 Hz, 1H), 7.55-7.70(m,3H), 8.07(d, J=6.9 Hz, 2H)

EXAMPLE 36 Preparation of 2-[(1S,2S)-2-((S)-2-acetylamino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 106 in Table 1)

mp: 94°-105° C.

IR(KBr, cm⁻¹): 3280, i858, 1645-1620

NMR(CDCl₃, δ): 0.73(d, J=6.3 Hz, 6H), 0.99(d, J=7.1 Hz, 3H), 1.09(d,J=7.0 Hz, 3H), 1.27-1.55(m, 3H), 2.03(s, 3H), 2.28(m, 1H), 3.79(Ta, 1H),4.39(m, 1H), 5.14(d, J=3.3 Hz, 1H), 6.22(m, 1H), 6.69(d, J=8.3 Hz, 1H),7.45-7.60(m, 3H), 7.72(d, J=8.6 Hz, 1H), 7.97(dd, J=8.0 Hz, 1.5 Hz, 2H)

EXAMPLE 37 Preparation of 2-[(1S,2S)-1-hydroxy-2-((S)-2-isohexanoylamino-4-methylvalerylamino)-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 114 in Table 1)

mp: 148°-151° C.

IR(KBr, cm⁻¹): 3293, 1856, 1640

NMR(CDCl₃, δ): 0.73(d, J=5.9 Hz, 3H), 0.74(d, J=6.0 Hz, 3H), 0.85(d,J=6.2 Hz, 6H), 0.98(d, J=6.7 Hz, 3H), 1.08(d, J=6.6 Hz, 3H),1.30-1.60(m, 6H), 2.11(t, J=6.7 Hz, , 2H), 2.27(m, 1H), 3.83(m, 1H),4.43(m, 1H), 5.13(dd, J=7.9 Hz, 4.2 Hz, 1H), 6.16(d, J=7.9 Hz, 1H),6.53(d, J=7.9 Hz, 1H), 7.45-7.55(m, 3H), 7.62(d, J=8.3 Hz, 1H), 7.98(dd,J=7.7 Hz, 1.4 Hz, 2H)

EXAMPLE 38 Preparation of 2-[(1S,2S)-1-hydroxy-2-((S)-2-lauroylamino-4-methylvalerylamino)⁻3-methylbutyl]-3-phenylcyclopropenone (compd. No. 120 in Table 1)

mp: 123°-127° C.

IR(KBr, cm⁻¹): 3293, 1856, 1640

NMR(CDCl₂, δ): 0.71(d, J=5.9 Hz, 3H), 0.73(d, J=5.9 Hz, 3H), 0.87(t,J=6.2 Hz, 3H), 0.97(d, J=6.6 Hz, 3H), 1.08(d, J=6.6 Hz, 3H),1.15-1.45(m, 16H), 1.45-1.80(m, 5H), 2.10(t, J=7.6 Hz, , 2H), 2.24(m,1H), 3.84(m, 1H), 4.42(m, 1H), 5.13(dd, J=7.9 Hz, 3.9 Hz, 1H), 6.22(d,J=8.3 Hz, 1H), 6.64(d, J=7.9 Hz, 1H), 7.42-7.60(m, 3H), 7.67(d, J=8.3Hz, 1H), 7.98(dd, J=8.0 Hz, 1.7 Hz, 2H)

EXAMPLE 39 Preparation of 2-[(1S,2S)-2-{(S)-2-(3-cyclohexylpropionylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl ]-3-phenylcyclopropenone (compd. No. 124 inTable 1)

mp: 126°-128° C.

IR(KBr, cm⁻¹): 3300, 1858, 1640

NMR(CDCl₃, δ): 0.74(d, J=6.3 Hz, 3H), 0.75(d, J=6.3 Hz, 3H),0.70-0.95(m, 2H), 0.98(d, J=7.0 Hz, 3H), 1.08(d, J=7.0 Hz, 3H),1.05-1.35(m, 4H), 1.35-1.55(m, 5H), 1.55-1.75(m, 5H), 2.11(t, J=8.7 Hz,2H), 2.27(m, 1H), 3.80(m, 1H), 4.41(m, 1H), 5.13(m, 1H), 6.11(s, 1H),6.42(d, J=8.5 Hz, 1H), 7.45-7.65(m, 4H), 7.99(dd, J=8.0 Hz, 1.4 Hz, 2H)

EXAMPLE 40 Preparation of 2-[(1S,2S)-2-((S)-2-cyclohexylcarbonylamino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 129 in Table 1)

mp: 116°-1200C.

IR(KBr, cm⁻¹): 3297, 1856, 1640

NMR(CDCl₃, δ): 0.72(d, J=5.4 Hz, 3H), 0.74(d, J=4.2 Hz, 3H), 0.97(d,J=6.6 Hz, 3H), 1.07(d, J=6.6 Hz, 3H), 0.95-1.55(m, 8H), 1.55-1.80(m,5H), 2.05(m, 1H), 2.24(m, 1H), 3.83(m, 1H), 4.39(m, 1H), 5.13(dd, J=7.8Hz, 4.1 Hz, 1H), 6.21(d, J=8.0 Hz, 1H), 6.46(d, J=7.8 Hz, 1H),7.38-7.55(m, 3H), 7.62(d, J=8.5 Hz, 1H), 7.98(dd, J=7.8 Hz, 1.5 Hz, 2H)

EXAMPLE 41 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-((S)-4-methyl-2-phenylacetylaminovalerylamino)butyl]-3-phenylcyclopropenone(compd. No. 132 in Table 1)

mp: 152°-154° C.

IR(KBr, cm⁻¹): 3280, 1856, 1635

NMR(CDCl₃, δ): 0.68(d, J=5.5 Hz, 6H), 0.91(d, J=6.7 Hz, 3H), 1.03(d,J=6.6 Hz, 3H), 1.18-1.43(m, 3H), 2.23(m, 1H), 3.39(d, J=15 Hz, 1H),3.47(d, J=15 Hz, 1H), 3.72(m, 1H), 4.38(m, 1H), 5.07(m, 1H), 6.03(m,1H), 6.37(d, J=7.8 Hz, 1H), 7.08-7.19(m, 2H), 7.19-7.30(m, 3H),7.40-7.60(m, 4H), 7.96(dd, J=7.7 Hz, 1.2 Hz, 2H)

EXAMPLE 42

Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(3-phenylpropionylamino)valerylamino}butyl]-3-phenylcyclopropenone(compd. No. 133 in Table 1)

mp: 148° C.

IR(KBr, cm⁻¹): 3287, 1854, 1640

NMR(CDCl₃, δ): 0.67(d, J=3.9 Hz, 6H), 0.95(d, J=6.8 Hz, 3H), 1.06(d,J=6.8 Hz, 3H), 1.18-1.40(m, 3H), 2.27(m, 1H), 2.43(t, J=7.9 Hz, 2H),3.70-3.90(m, 2H), 3.74(m, 1H), 4.39(m, 1H), 5.09(m, 1H), 6.19(d, J=8.3Hz, 1H), 6.59(d, J=8.2 Hz, 1H), 7.07-7.30(m, 5H), 7.40-7.60(m, 4H),7.96(dd, J=6.6 Hz, 1.7 Hz, 2H)

EXAMPLE 43 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(4-phenylbutyrylamino)valerylamino}butyl]-3-phenylcyclopropenone(compd. No. 134 in Table 1)

mp: 91°-96° C.

IR(KBr, cm⁻¹): 3293, 1856, 1640

NMR(CDCl₃, δ): 0.72(d, J=5.1 Hz, 6H), 0.97(d, J=6.6 Hz, 3H), 1.06(d,J=6.5 Hz, 3H), 1.25-1.55(m, 3H), 1.84(m, 2H), 2.11(m, 2H), 2.27(m, 1H),2.55(t, J=7.5 Hz, 2H), 3.80(m, 1H), 4.42(m, 1H), 5.10(m, 1H), 6.19(d,J=8.1 Hz, 1H), 6.62(d, J=7.7 Hz, 1H), 7.05-7.35(m, 5H), 7.40-7.60(m,3H), 7.66(d, J=8.3 Hz, 1H), 7.96(d, J=6.4 Hz, 2H)

EXAMPLE 44 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-(S)-4-methyl-2-(4-oxovalerylamino)valerylamino]-3-phenylcyclopropenone(compd. No. 137 in Table 1)

mp: 89°-93° C.

IR(KBr, cm⁻¹): 3299, 1856, 1719, 1643

NMR(CDCl₃, δ): 0.76(d, J=6.1 Hz, 3H), 0.77(d, J=5.8 Hz, 3H), 0.95(d,J=6.7 Hz, 3H), 1.08(d, J=6.6 Hz, 3H), 1.28(m, 1H), 1.48(m, 2H), 2.16(s,3H), 2.27-2.50(m, 3H), 2.65-2.80(m, 1H), 2.85-3.05(m, 1H), 3.66(m, 1H),4.35(m, 1H), 5.10(m, 1H), 6.18(d, J=8.5 Hz, 1H), 6.55(d, J=7.6 Hz, 1H),7.45-7.60(m, 3H), 7.62(d, J=8.0 Hz, 1H), 7.98(dd, J=7.9 Hz, 1.7 Hz, 2H)

EXAMPLE 45 Preparation of 2-[(1S,2S)-2-{(S)-2-(3-benzoylpropionylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 140 in Table 1)

mp: 83°-88° C.

IR(KBr, cm⁻¹): 3292, 1856, 1684, 1641

NMR(CDCl₃, δ): 0.78(d, J=6.1 Hz, 3H), 0.79(d, J=5.9 Hz, 3H), 0.90(d,J=6.7 Hz, 3H), 1.05(d, J=6.6 Hz, 3H), 1.31(m, 1H), 1.48-1.68(m, 2H),2.40(m, 1H), 2.54(m, 2H), 3.22-3-48(m, 1H), 3.42-3.75(m, 2H), 4.38(m,1H), 5.05(m, 1H), 6.09(m, 1H), 6.57(d, J=7.8 Hz, 1H), 7.35-7.60(m, 6H),7.74(d, J=7.8 Hz, 1H), 7.90-8.05(m, 4H)

EXAMPLE 46 Preparation of 2-[(1S,2S)-2-{(S)-2-(3-ethoxycarbonylpropionylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 142 in Table 1)

mp: 111°-112° C.

IR(KBr, cm⁻¹): 3293, 1856, 1738, 1643

NMR(CDCl₃, δ): 0.70-0.90(m, 6H), 0.97(d, J=6.6 Hz, 3H), 1.08(d, J=6.6Hz, 3H), 1.15-1.35(m, 1H), 1.25(t, J=7.2 Hz, 3H), 1.40-1.60(m, 2H),2.30-2.65(m, 4H), 2.70-2.90(m, 1H), 3.57(m, 1H), 4.09(m, 2H), 4.39(m,1H), 5.09(m, 1H), 6.12(s, 1H), 6.47(d, J=7.1 Hz, 1H), 7.45-7.60(m, 3H),7.66(d, J=7.5 Hz, 1H), 7.99(dd, J=7.5 Hz, 1.0 Hz, 2H)

EXAMPLE 47 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-((S)-4-methyl-2-succinylaminovalerylamino)butyl]-3-phenylcyclopropenone(compd. No. 143 in Table 1)

mp: 104°-106° C.(dec.)

IR(KBr, cm⁻¹): 3297, 1858, 1719, 1650, 1630

NMR(CD₃ OD, δ): 0.56(d, J=6.7 Hz, 3H), 0.63(d, J=6.7 Hz, 3H), 0.97(d,J=6.9 Hz, 3H), 1.08(d, J=6.8 Hz, 3H), 1.05-1.33(m, 2H), 1.40(m, 1H),2.09(m, 1H), 2.35-2.60(m, 4H), 4.0(m, 1H), 4.22(m, 1H), 5.20(d, J=2.9Hz, 1H), 7.47-7.65(m, 3H), 7.90-8.10(m, 3H)

EXAMPLE 48 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-((S)-4-methyl-2-phenoxyacetylaminovalerylamino)butyl]-3-phenylcyclopropenone(compd. No. 148 in Table 1)

mp: 138°-139° C.

IR(KBr, cm⁻¹): 3290, 1856, 1648, 1620

NMR(CDCl₃, δ): 0.78(d, J=5.8 Hz, 6H), 1.02(d, J=6.7 Hz, 3H), 1.09(d,J=6.6 Hz, 3H), 1.30-1.60(m, 3H), 2.38(m, 1H), 3.64(m, 1H), 4.26(d, J=15Hz, 1H), 4.37(d, J=15 Hz, 1H), 4.49(m, 1H), 5.14(m, 1H), 6.12(m, 1H),6.84(d, J=8.8 Hz, 2H), 6.90(d, J=8.8 Hz, 1H), 7.01(t, J=7.4 Hz, 1H),7.25-7.38(m, 2H), 7.38-7.53(m, 3H), 7.66(d, J=7.6 Hz, 1H), 7.85-7.98(m,2H)

EXAMPLE 49 Preparation of 2-[(1R,2S)-1-hydroxy-3-methyl-2-((S)-4-methyl-2-phenoxyacetylaminOoalerylamino)butyl]-3-phenylcyclopropenone(compd- No. 148 in Table 1)

mp: 74°-84° C.

IR(KBr, cm⁻¹): 3300, 1859, 1658, 1627

NMR(CDCl₃, δ): 0.64(d, J=6.3 Hz, 6H), 1.06(d, J=6.6 Hz, 3H), 1.15(d,J=6.7 Hz, 3H), 1.30-1.65(m, 3H), 2.14(m, 1H), 4.03(m, 1H), 4.39(d, J=15Hz, 1H), 4.47(d, J=15 Hz, 1H), 4.51(m, 1H), 5.15(dd, J=6.6 Hz, 2.8 Hz,1H), 5.26(d, J=6.6 Hz, 1H), 6.85-6.95(m, 3H), 7.02(t, J=7.4 Hz, 1H),7.20-7.40(m, 3H), 7.45-7.60(m, 3H), 8.01(dd, J=7.8 Hz, 1.3 Hz, 2H)

EXAMPLE 50 Preparation of 2-[(1S,2S)-2-{(S)-2-(2-chlorophenoxyacetylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 152 in Table 1)

mp: 101° C.

IR(KBr, cm⁻¹): 3287, 1856, 1653, 1624

NMR(CDCl₃, δ): 0.80(d, J=5.2 Hz, 3H), 0.82(d, J=5.1 Hz, 3H), 1.03(d,J=6.6 Hz, 3H), 1.10(d, J=6.6 Hz, 3H), 1.35-1.60(m, 3H), 2.38(m, 1H),3.68(m, 1H), 4.30(d, J=15 Hz, 1H), 4.40(d, J=15 Hz, 1H), 4.45(m, 1H),5.14(dd, J=7.8 Hz, 4.1 Hz, 1H), 6.17(d, J=8.4 Hz, 1H), 6.81(d, J=8.2 Hz,1H), 6.97(t, J=7.7 Hz, 1H), 7.07(d, J=7.7 Hz, 1H), 7.22(t, J=7.6 Hz,1H), 7.32-7.48(m, 4H), 7.71(d, J=7.7 Hz, 1H), 7.85-7.95(m, 2H)

EXAMPLE 51 Preparation of 2-[(1S,2S)-2-{(S)-2-(4-chlorophenoxyacetylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 154 in Table 1)

mp: 88°-90° C.

IR(KBr, cm⁻¹): 3295, 1856, 1653, 1624

NMR(CDCl₃, δ): 0.79(d, J=3.7 Hz, 6H), 1.02(d, J=6.6 Hz, 3H), 1.10(d,J=6.6 Hz, 3H), 1.33-1.60(m, 3H), 2.36(m, 1H), 3.65(m, 1H), 4.21(d, J=15Hz, 1H), 4.34(d, J=15 Hz, 1H), 4.51(m, 1H), 5.14(dd, J=8.3 Hz, 4.1 Hz,1H), 6.12(d, J=8.3 Hz, 1H), 6.78(d, J=8.9 Hz, 2H), 6.88(d, J=8.3 Hz,1H), 7.24(d, J=8.9 Hz, 2H), 7.35-7.55(m, 3H), 7.69(d, J=8.0 Hz, 1H),7.90(dd, J=6.6 Hz, 2.5 Hz, 2H)

EXAMPLE 52 Preparation of 2-[(1S, 2S)-2-{(S)-2-(2,3-dichlorophenoxyacetylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 155 in Table 1)

mp: 121°-123° C.

IR(KBr, cm⁻¹): 3291, 1856, 1651, 1624 NMR(CDCl₃, δ): 0.81(d, J=5.0 Hz,3H), 0.83(d, J=5.1 Hz, 3H), 1.03(d, J=6.6 Hz, 3H), 1.11(d, J=6.6 Hz,3H), 1.38-1.63(m, 3H), 2.38(m, 1H), 3.67(m, 1H), 4.31(d, J=14 Hz, 1H),4.40(d, J=14 Hz, 1H), 4.45(m, 1H), 5.15(dd, J=8.3 Hz, 4.0 Hz, 1H),6.20(d, J=8.3 Hz, 1H), 6.73(m, 1H), 7.03(d, J=8.3 Hz, 1H), 7.07-7.22(m,2H), 7.35-7.55(m, 3H), 7.74(d, J=8.2 Hz, 1H), 7.88(d, J=5.2 Hz, 2H)

EXAMPLE 53 Preparation of 2-[(1S,2S)-1-hydroxy-2-{(S)-2-(2-methoxyphenoxyacetylamino)-4-methylvalerylamino)}-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 161 in Table 1)

mp: 106°-108° C.

IR(KRb, cm⁻¹): 1 3278, 1854, 1672, 1645

NMR(CDCl₃, δ): 0.70-0.85(m, 6H), 0.96(d, J=6.7 Hz, 3H), 1.05(d, J=6.6Hz, 3H), 1.30-1.55(m, 3H), 2.36(m, 1H), 3.57(m, 1H), 3.84(s, 3H),4.41(d, J=15 Hz, 1H), 4.49(d, J=15 Hz, 1H), 5.10(dd, J=7.3 Hz, 4.6 Hz,1H), 6.08(d, J=8.2 Hz, 1H), 6.82-6.95(m, 3H), 6.95-7.08(m, 1H),7.33-7.57(m, 5H), 7.94(dd, J=6.1 Hz, 1.7 Hz, 2H)

EXAMPLE 54 Preparation of 2-[(1S,2S)-2-((S)-2-benzyloxyacetylamino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 166 in Table 1)

mp: 59°-69° C.

IR(KBr, cm⁻¹): 1 3293, 1856, 1651, 1623

NMR(CDCl₃, δ): 0.65-0.85(m, 6H), 0.99(d, J=6.6 Hz, 3H), 1.06(d, J=6.6Hz, 3H), 1.30-1.60(m, 3H), 2.29(m, 1H), 3.75(m, 1H), 3.76(d, J=15 Hz,1H), 3.88(d, J=15 Hz, 1H), 4.30-4.55(m, 3H), 5.08(m, 1H), 6.12(m, 1H),6.95(d, J=8.4 Hz, 1H), 7.20-7.40(m, 5H), 7.40-7.60(m, 3H), 7.69(d, J=8.1Hz, 1H), 7.93(d, J=6.5 Hz, 2H)

EXAMPLE 55 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(3-phenoxypropionylamino)valerylamino}butyl]-3-phenylcyclopropenone(compd. No. 167 in Table 1)

mp: 92°-95° C.

IR(KBr, cm⁻¹): 3291, 1856, 1643, 1605

NMR(CDCl₃, δ): 0.73(d, J=6.3 Hz, 6H), 0.89(d, J=6.7 Hz, 3H), 0.99(d,J=6.6 Hz, 3H), 1.25-1.58(m, 3H), 2.31(m, 1H), 2.59(t, J=4.0 Hz, 2H),3.51(m, 1H), 4.16(m, 2H), 4.41(m, 1H), 5.07(dd, J=8.1 Hz, 4.2 Hz, 1H),6.28(d, J=8.3 Hz, 1H), 6.69(d, J=8.1 Hz, 1H), 6.87(d, J=8.7 Hz, 2H),6.95(t, J=7.6 Hz, 1H), 7.19-7.35(m, 2H), 7.40-7.60(m, 4H), 7.96(dd,J=6.8 Hz, 1.4 Hz, 2H)

EXAMPLE 56 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-((S)-4-methyl-2-phenylthioacetylaminovalerylamino}butyl]-3-phenylcyclopropenone(compd. No. 168 in Table 1)

mp: 133° C.

IR(KBr, cm⁻¹): 3287, 1854, 1643, 1625

NMR(CDCl₃, δ): 0.55-0.80(m, 6H), 0.93(d, J=6.6 Hz, 3H), 1.06(d, J=6.6Hz, 3H), 1.05-1.40(m, 3H), 2.28(m, 1H), 3.43(d, J=17 Hz, 1H), 3.58(d,J=17 Hz, 1H), 3.62(m, 1H), 4.33(m, 1H), 5.11(dd, J=8.3 Hz, 4.1 Hz, 1H),6.15(m, 1H), 7.08-7.35(m, 6H), 7.35-7.60(m, 4H), 7.95(dd, J=7.5 Hz, 1.6Hz, 2H)

EXAMPLE 57 Preparation of 2-(1S,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(3-phenylsulfonylpropionylamino)valerylamino}butyl]-3-phenylcyclopropenone(compd. No. 170 in Table 1)

mp: 100°-106° C.

IR(KBr, cm⁻¹): 3295, 1856, 1644

NMR(CDCl₃, δ): 0.74(d, J=4.2 Hz, 6H), 0.99(d, J=6.8 Hz, 3H), 1.07(d,J=6.8 Hz, 3H), 1.25-1.65(m, 3H), 2.38(m, 1H), 2.69(m, 2H), 3.27-3.43(m,1H), 3.43-3.65(m, 2H), 4.37(m, 1H), 5.14(dd, J=8.9 Hz, 5.0 Hz, 1H),6.18(d, J=8.9 Hz, 1H), 7.18(d, J=7.6 Hz, 1H), 7.40-7.60(m, 5H), 7.67(t,J=7.4 Hz, 2H), 7.90(d, J=7.2 Hz, 2H), 7.98(d, J=6.4 Hz, 2H)

EXAMPLE 58 Preparation of 2-[(1S,2S)-2-((S)-2-benzoylamino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 171 in Table 1)

mp: 150°-154° C.

IR(KBr, cm⁻¹): 3297, 1856, 1632

NMR(CDCl₃, δ): 0.63-0.80(m, 6H), 0.91(d, J=6.5 Hz, 3H), 0.93(d, J=6.5Hz, 3H), 1.35-1.65(m, 3H), 2.22(m, 1H). 3.42(m, 1H), 4.48(m, 1H),4.78(m, 1H), 6.23(d, J=7.8 Hz, 1H), 7.28-7.55(m, 6H), 7.60-7.68(m, 3H),7.81(d, J=8.2 Hz, 1H), 7.85-7.95(m, 2H)

EXAMPLE 59 Preparation of 2-[(1S,2S)-2-{(S)-2-(2,6-difluorobenzoylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 175 in Table 1)

mp: 111°-122° C.

IR(KBr, cm⁻¹): 1 3300, 1858, 1647, 1626

NMR(CDCl₃, δ): 0.72(d, J=6.3 Hz, 3H), 0.74(d, J=6.2 Hz, 3H), 1.04(d,J=6.8 Hz, 3H), 1.10(d, J=6.7 Hz, 3H), 1.30-1.65(m, 3H), 2.33(m, 1H),3.73(m, 1H), 4.57(m, 1H), 5.01(d, J=4.0 Hz, 1H), 6.82(dd, J=8.0 Hz, 7.9Hz, 2H), 7.26(m, 1H), 7.37-7.55(m, 4H), 7.64(d, J=8.3 Hz, 1H), 7.91(d,J=6.7 Hz, 2H)

EXAMPLE 60 Preparation of 2-[(1S,2S)-2-{(S)-2-(2-chlorobenzoylamino)-4-methylvalerylamino}-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 178 in Table 1)

mp: 99°-104° C.

IR(KBr, cm⁻¹): 1 3297, 1856, 1637

NMR(CDCl₃, δ): 0.76(d, J=5.7 Hz, 3H), 0.78(d, J=5.1 Hz, 3H), 1.04(d,J=6.6 Hz, 3H), 1.09(d, J=6.6 Hz, 3H), 1.38-1.65(m, 3H), 2.32(m, 1H),3.72(m, 1H), 4.59(m, 1H), 5.05(dd, J=8.4 Hz, 4.3 Hz, 1H), 6.14(d, J=8.4Hz, 1H), 7.05-7.35(m, 4H), 7.35-7.58(m, 4H), 7.71(d, J=8.2 Hz, 1H),7.91(d, J=6.7 Hz, 2H)

EXAMPLE 61 Preparation of 2-[(1S,2S)-2-{(S)-2-(3-chlorobenzoylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 179 in Table 1)

mp: 179° C.

IR(KBr, cm⁻¹): 3297, 1856, 1634

NMR(CDCl₃, δ): 0.71(d, J=6.2 Hz, 3H), 0.74(d, J=6.4 Hz, 3H), 0.90(d,J=6.7 Hz, 3H), 0.93(d, J=8.8 Hz, 3H), 1.30-1.70(m, 3H), 2.19(m, 1H),3.44(m, 1H), 4.46(m, 1H), 4.83(m, 1H), 6.20(m, 1H), 7.15-7.35(m, 1H),7.35-7.55(m, 4H), 7.64(d, J=7.7 Hz, 1H), 7.75(s, 1H), 7.80-8.03(m,

EXAMPLE 62 Preparation of 2-[(1S,2S)-2-{(S)-2-(4-chlorobenzoylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 180 in Table 1)

mp: 116°-120° C.

IR(KBr, cm⁻¹): 3297, 1856, 1631

NMR(CDCl₃, δ): 0.71(d, J=5.5 Hz, 3H), 0.73(d, J=5.4 Hz, 3H), 0.89(d,J=6.6 Hz, 3H), 0.95(d, J=6.6 Hz, 3H), 1.30-1.65(m, 3H), 2.21(m, 1H),3.51(m, 1H), 4.49(m, 1H), 4.87(m, 1H), 6.26(d, J=8.6 Hz, 1H), 7.28(d,J=7.5 Hz, 2H), 7.38-7.58(m, 3H), 7.67(d, J=7.5 Hz, 2H), 7.70-7.95(m, 4H)

EXAMPLE 63 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(2-toluoylamino)valerylamino}butyl]-3-phenylcyclopropenone(compd. No. 184 in Table 1)

mp: 101°-105° C.

IR(KBr, cm⁻¹): 3295, 1856, 1656, 1631

NMR(CDCl₃, δ): 0.75(d, J=5.9 Hz, 3H), 0.76(d, J=5.8 Hz, 3H), 1.02(d,J=6.7 Hz, 3H), 1.06(d, J=6.7 Hz, 3H), 1.40-1.65(m, 3H), 2.25(m, 1H),2.30(s, 3H), 3.66(m, 1H), 4.52(m, 1H), 4.88(dd, J=8.9 Hz, 4.0 Hz, 1H),6.14(d, J=8.9 Hz, 1H), 7.01-7.08(m, 3H), 7.08-7.32(m, 2H), 7.38-7.60(m,3H), 7.78(d, J=7.1 Hz, 1H), 7.87(dd, J=8.2 Hz, 1.5 Hz, 2H)

EXAMPLE 64 Preparation of 2-[(1S,2S)-1-hydroxy-2-{2-(4-methoxybenzoylamino)-4-methylvalerylamino}-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 190 in Table 1)

IR(KBr, cm⁻¹): 3297, 1856, 1628

NMR(CDCl₃, δ): 0.62-0.90(m, 6H), 0.90-1.05(m, 6H), 1.30-1.60(m, 3H),2.21(m, 1H), 3.46(m, 1H), 3.80(s, 3H), 4.49(m, 1H), 4.70-4.95(m, 1H),6.20-6.50(m, 1H), 6.83(d, J=8.9 Hz, 2H), 7.33-7.58(m, 4H), 7.68-7.95(m,3H), 7.87(d, J=7.8 Hz, 2H)

EXAMPLE 65 Preparation of 2-[(1S,2S)-1-hydroxy-2-{(S)-2-(4-methoxycarbonylbenzoylamino)-4-methylvalerylamino}-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 191 in Table 1)

mp: 125°-128° C.

IR(KBr, cm⁻¹): 3301, 1856, 1728, 1634

NMR(CDCl₃, δ): 0.71(d, J=5.5 Hz, 3H), 0.73(d, J=5.3 Hz, 3H), 0.89(d,J=6.9 Hz, 3H), 0.93(d, J=7.0 Hz, 3H), 1.33-1.65(m, 3H), 2.18(m, 1H),3.51(m, 1H), 3.92(s, 3H), 4.52(m, 1H), 4.84(dd, J=8.9 Hz, 3.5 Hz, 1H),6.25(d, J=8.9 Hz, 1H), 7.35-7.55(m, 3H), 7.76(d, J=8.3 Hz, 2H),7.85-8.03(m, 6H)

EXAMPLE 66 Preparation of 2-[(1S,2S)-2-{(S)-2-(1-acetyl-4-piperidyl)carbonylamino-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 196 in Table 1)

mp: 120°-124° C.

IR(KBr, cm⁻¹): 3300, 1860, 1630

NMR(CDCl₃, δ): 0.72(d, J=2.7 Hz, 6H), 0.96(d, J=6.6 Hz, 3H), 1.08(d,J=6.9 Hz, 3H), 1.30-1.90(m, 7H), 2.06(s, 3H), 1.95-2.40(m, 2H), 2.55(m,1H), 3.01(m, 1H), 3.70-3.93(m, 2H), 4.35-4.60(m, 2H), 5.14(m, 1H),6.15(m, 1H), 6.70(t, J=8.8 Hz, 1H), 7.43-7.65(m, 4H), 7.97(d, J=6.8 Hz,2H)

EXAMPLE 67 Preparation of 2-[(1S,2S)-2-{(S)-2-(2-furoylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 197 in Table 1)

mp: 101°-105° C.

IR(KBr, cm⁻¹): 3300, 1857, 1640

NMR(CDCl₃, δ): 0.80(d, J=5.8 Hz, 6H), 1.01(d, J=7.1 Hz, 3H), 1.08(d,J=7.0 Hz, 3H), 1.40-1.65(m, 3H), 2.37(m, 1H), 3.67(m, 1H), 4.58(m, 1H),5.14(d, J=4.4 Hz, 1H), 6.43(dd, J=3.7 Hz, 1.8 Hz, 1H), 6.79(d, J=8.7 Hz,1H), 7.01(d, J=3.7 Hz, 1H), 7.35(d, J=1.8 Hz, 1H), 7.40-7.55(m, 3H),7.78(d, J=8.2 Hz, 1H), 7.91(dd, J=8.1 Hz, 1.5 Hz, 2H)

EXAMPLE 68 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(2-thenoylamino)valerylamino}butyl]-3-phenylcyclopropenone(compd. No. 200 in Table 1)

mp: 171°-172° C.

IR(KBr, cm⁻¹): 3301, 1856, 1665, 1624

NMR(CDCl₃, δ): 0.69(d, J=6.9 Hz, 3H), 0.72(d, J=6.6 Hz, 3H), 0.87(d,J=6.6 Hz, 3H), 0.92(d, J=6.6 Hz, 3H), 1.30-1.70(m, 3H), 2.15(m, 1H),3.62(m, 1H), 4.48(m, 1H), 4.94(dd, J=8.4 Hz, 3.1 Hz, 1H), 6.34(d, J=8.4Hz, 1H), 6.99(dd, J=4.5 Hz, 4.3 Hz, 1H), 7.38-7.62(m, 4H), 7.66(dd,J=3.5 Hz, 1H), 7.68-8.03(m, 4H)

EXAMPLE 69 Preparation of 2-[(1S,2S)-2-{(S)-2-(1,3-dimethyl-5-pyrazolylcarbonylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 203 in Table 1)

mp: 115°-118° C.

IR(KBr, cm⁻¹): 3289, 1856, 1636

NMR(CDCl₃, δ): 0.80(d, J=5.9 Hz, 3H), 0.82(d, J=6.0 Hz, 3H), 1.01(d,J=6.7 Hz, 3H), 1.06(d, J=6.7 Hz, 3H), 1.42-1.60(m, 3H), 2.20(s, 3H),2.37(m, 1H), 3.54(m, 1H), 4.00(s, 3H), 4.50(m, 1H), 5.06(m, 1H), 6.03(s,1H), 6.27(s, 1H), 6.80(d, J=8.3 Hz, 1H), 7.43-7.54(m, 3H), 7.58(d, J=7.8Hz, 1H), 7.89(dd, J=7.8 Hz, 1.5 Hz, 2H)

EXAMPLE 70 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(6-methyl-2-pyridylcarbonylamino)valerylamino}buryl]-3-phenylcyclopropenone(compd. No. 207 in Table 1)

mp: 98°-100° C.

IR(KBr, cm⁻¹): 3314, 1856, 1655

NMR(CDCl₃, δ): 0.81(d, J=5.7 Hz, 3H), 0.82(d, J=5.9 Hz, 3H), 1.02 (d,J=6.7 Hz, 3H), 1.56(m, 3H), 2.42(m, 1H), 2.49(s, 3H), 3.67(m, 1H),4.56(m, 1H), 5.18(m, 1H), 6.33(d, J=7.8 Hz, 1H), 7.22(d, J=7.5 Hz, 1H),7.36-7.44(m, 3H), 7.64(dd, J=7.7 Hz, 7.7 Hz, 1H), 7.77-7.90(m, 4H),8.22(d, J=4.1 Hz, 1H)

EXAMPLE 71 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-((S)-4-methyl-2-nicotinoylaminovalerylamino)butyl]-3-phenylcyclopropenone(compd. No. 209 in Table 1)

mp: 108°-115° C.(dec.)

IR(KBr, cm⁻¹): 3299, 1856, 1642

NMR(CDCl₃, δ): 0.63-0.80(m, 6H), 0.92(d, J=6.7 Hz, 3H), 0.96(d, J=6.8Hz, 3H), 1.34-1.72(m, 3H), 2.23(m, 1H), 3.58(m, 1H), 4.59(m, 1H),5.30(m, 1H), 6.58(m, 1H), 7.25(m, 1H), 7.35-7.55(m, 3H), 7.92(dd, J=6.7Hz, 1.4 Hz, 2H), 8.02-8.18(m, 2H), 8.32(m, 1H), 8.59(dd, J=4.8 Hz, 1.5Hz, 1H), 9.11(d, J=1.5 Hz, 1H)

EXAMPLE 72 Preparation of 2-[(1S,2S)-1-hydroxy-2-((S)-2-isonicotinoylamino-4-methylvalerylamino)-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 213 in Table 1)

mp: 202°-203° C.(dec.)

IR(KBr, cm⁻¹): 3299, 1856, 1647, 1625

NMR(CD₃ OD, δ): 0.54(d, J=6.4 Hz, 3H), 0.69(d, J=6.4 Hz, 3H), 1.01(d,J=6.7 Hz, 3H), 1.12(d, J=6.6 Hz, 3H), 0.95-1.60(m, 3H), 2.12(m, 1H),4.07(m, 1H), 4.55(m, 1H), 5.24(d, J=2.2 Hz, 1H), 7.45-7.70(m, 3H),8.07(d, J=8.0 Hz, 2H), 8.33(d, J=6.8 Hz, 2H), 8.44(d, J=9.7 Hz, 1H),9.57(d, J=6.8 Hz, 2H)

EXAMPLE 73 Preparation of 2-[(1s,2S)-2-{(S)-2-(2-chloroisonicotinoylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 216 in Table 1)

mp: 136°-138° C.(dec.)

IR(KBr, cm⁻¹): 3299, 1856, 1643

NMR(CDCl₃, δ): 0.76(d, J=6.4 Hz, 3H), 0.79(d, J=6.6 Hz, 3H), 0.95(d,J=6.7 Hz, 3H), 1.02(d, J=6.6 Hz, 3H), 1.40-1.63(m, 3 H), 2.26(m, 1H),3.50(m, 1H), 4.51(m, 1H), 5.00(d, J=3.5 Hz, 1), 6.03(s, 1H),7.43-7.53(m, 4H), 7.62(d, J=0.6 Hz, 1H), 7.75(m, 2H), 7.90(dd, J=7.9 Hz,1.3 Hz, 2H), 8.41(d, J=5.2 Hz, 1H)

EXAMPLE 74 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(2-quinolylcarbonylamino)valerylamino}butyl-3-phenylcyclopropenonehydrochloride (compd. No. 219 in Table 1)

mp: 156°-157° C.(dec.)

IR(KBr, cm⁻¹): 3252, 1854, 1684, 1620

NMR(CD₃ OD, δ): 0.60(d, J=6.4 Hz, 3H), 0.74(d, J=6.4 Hz, 3H), 1.02(d,J=6.7 Hz, 3H), 1.12(d, J=6.6 Hz, 3H), 1.08-1.33(m, 1H), 1.52(m, 2H),2.15(m, 1H), 4.09(dd, J=9.8 Hz, 2.4 Hz, 1H), 4.66(m, 1H), 5.25(d, J=2.3Hz, 1H), 7.40-7.58(m, 3H), 7.92(m, 1H), 8.02-8.17(m, 3H), 8.26(d, J=8.3Hz, 1H), 8.36(dd, J=8.6 Hz, 1.6 Hz, 2H), 9.02(d, J=8.5 Hz, 1H)

EXAMPLE 75 Preparation of 2-[(1S,2S)-2-{(S)-2-(3-benzylureido)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 225 in Table 1)

mp: 160° C.

IR(KBr, cm⁻¹): 3308, 1856, 1628

NMR(CD₃ OD, δ): 0.53(d, J=6.6 Hz, 3H), 0.62(d, J=6.5 Hz, 3H), 0.95(d,J=6.7 Hz, 3H), 1.08(d, J=6.7 Hz, 3H), 0.95-1.25(m, 2H), 1.39(m, 1H),2.07(m, 1H), 4.01(dd, J=9.5 Hz, 2.4 Hz, 1H), 4.13(dd, J=9.9 Hz, 4.9 Hz,1H), 4.20(d, J=14 Hz, 1H), 4.26(d, J=14 Hz, 1H), 5.19(d, J=2.4 Hz, 1H),7.13-7.33(m, 5H), 7.50-7.70(m, 3H), 7.07(dd, J=7.6 Hz, 1.8 Hz, 2H)

EXAMPLE 76 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(3-Phenylureido)valerylamino)}butyl]-3-phenylcyclopropenone(compd. No. 227 in Table 1)

mp: 165°-169° C.(dec.)

IR(KBr, cm⁻¹): 3318, 1856, 1645, 1620

NMR(CD₃ OD, δ): 0.55(d, J=6.6 Hz, 3H), 0.66(d, J=6.5 Hz, 3H), 0.99(d,J=6.7 Hz, 3H), 1.10(d, J=6.7 Hz, 3H), 1.0-1.35(m, 2H), 1.48(m, 1H),2.11(m, 1H), 4.03(dd, J=9.6 Hz, 2.4 Hz, 1H), 4.20(dd, J=10 Hz, 5.0 Hz,1H), 5.22(d, J=2.4 Hz, 1H), 6.94(t, J=7.2 Hz, 1H), 7.15-7.33(m, 4H),7.50-7.67(m, 3H), 8.07 (dd, J=8.2 Hz, 1.8 Hz, 2H)

EXAMPLE 77 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-((S)-4-methyl-2-propylsulfonylaminovalerylamino)butyl]-3-phenylcyclopropenone(compd. No. 232 in Table 1)

mp: 195°-196° C.

IR(KBr, cm⁻¹): 3450, 3250, 1858, 1823, 1663, 1630

NMR(DMSO-d6): 0.37(d, J=6.9 Hz, 3H), 0.58(d, J=7.4 Hz, 3H), 0.70-1.15(m,8H), 1.03(d, J=7.0 Hz, 3H), 1.50-1.80(m, 3H), 1.96(m, 1H), 2.72(m, 2H),3.82(m, 1H), 3.93(m, 1H), 5.11(m, 1H), 6.34(d, J=5.4 Hz, 1H), 7.14(d,J=10 Hz, 1H), 7.50-7.65(m, 3H), 7.93(d, J=7.4 Hz, 2H), 8.08(d, J=10 Hz,1H)

EXAMPLE 78 Preparation of 2-[(1S,2S)-2-((S)-2-benzylsulfonylamino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 237 in Table 1)

mp: 197° C.(dec.)

IR(KBr, cm⁻¹): 3314, 1856, 1678, 1624

NMR(DMSO-d6): 0.39(d, J=6.6 Hz, 3H), 0.57(d, J=6.5 Hz, 3H), 0.78-1.0(m,2H), 0.95(d, J=6.7 Hz, 3H), 1.04(d, J=6.6 Hz, 3H), 1.42(m, 1H), 1.99(m,1H), 3.83-4.07(m, 2H), 4.05(d, J=14 Hz, 1H), 4.14(d, J=14 Hz, 1H),5.14(m, 1H), 6.38(m, 1H), 7.33(s, 5H), 7.20-7.45(m, 1H), 7.53-7.73(m,3H), 7.94(dd, J=7.1 Hz, 1.5 Hz, 2H), 8.14(d, J=9.4 Hz, 1H)

EXAMPLE 79 Preparation of 2-[(1R,2S)-2-((S)-2-benzylsulfonylamino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 237 in Table 1)

mp: 122°-124° C.

IR(KBr, cm⁻¹): 3280, 1858, 1662, 1625

NMR(CDCl₃, δ): 0.66(d, J=6.4 Hz, 3H), 0.69(d, J=6.3 Hz, 3H), 0.87(m,1H), 1.10(d, J=6.6 Hz, 3H), 1.14(d, J=6.7 Hz, 3H), 1.47(m, 2H), 2.17(m,1H), 3.77(m, 1H), 4.08-4.23(m, 3H), 4.92(d, J=6.4 Hz, 1H), 5.14(m, 1H),5.60(d, J=8.5 Hz, 1H), 7.18(d, J=8.3 Hz, 1H), 7.31(s, 5H), 7.41(t, J=7.6Hz, 2H), 7.53(t, J=7.2 Hz, 1H), 7.93(d, J=7.2 Hz, 2H)

EXAMPLE 80 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-((S)-4-methyl-2-phenylsulfonylaminovalerylamino)butyl]-3-phenylcyclopropenone(compd. No. 239 in Table 1)

mp: 207° C.(dec.)

IR(KBr, cm⁻¹): 3450, 3300, 1858, 1665, 1625

NMR(CD₃ OD, δ): 0.38(d, J=6.6 Hz, 3H), 0.40(d, J=6.5 Hz, 3H), 0.78(d,J=6.7 Hz, 3H), 1.02(d, J=6.6 Hz, 3H), 0.75-0.95(m, 2H), 1.34(m, 1H),1.97(m, 1H), 3.71(dd, J=10 Hz, 4.4 Hz, 1H), 3.92(dd, J=9.4 Hz, 2.5 Hz,1H), 5.14(d, J=2.5 Hz, 1H), 7.42-7.70(m, 6H), 7.81(dd, J=8.4 Hz, 1.6 Hz,2H), 8.03(dd, J=7.6 Hz, 1.2 Hz, 2H)

EXAMPLE 81 Preparation of 2-[(1R,2S)-1-hydroxy-3-methyl-2-((S)-4-methyl-2-phenylsulfonylaminovalerylamino)butyl]-3-phenylcyclopropenone(compd. No. 239 in Table 1)

mp: 193°-194° C.(dec.)

IR(KBr, cm⁻¹): 3300, 1860, 1664, 1627

NMR(CDCl₃, δ): 0.45(d, J=5.9 Hz, 3H), 0.69(d, J=6.0 Hz, 3H), 0.99(d,J=6.6 Hz, 3H), 1.11(d, J=6.6 Hz, 3H), 1.30-1.55(m, 3H), 2.10(m, 1H),3.64(m, 1H), 4.06(m, 1H), 4.81(d, J=8.0 Hz, 1H), 5.11(dd, J=7.9 Hz, 3.2Hz, 1H), 6.04(d, J=7.7 Hz, 1H), 7.17(d, J=8.8 Hz, 1H), 7.40-7.65(m, 6H),7.83(d, J=7.2 Hz, 2H), 7.97(d, J=7.0 Hz, 2H)

EXAMPLE 82 Preparation of 2-[(1S,2S)-1-acetoxy-3-methyl-2-((S)-4-methyl-2-phenylsulfonylaminovalerylamino)butyl]-3-phenylcyclopropenone(compd. No. 241 in Table 1)

mp: 202°-204° C.(dec.)

IR(KBr, cm⁻¹): 3274, 1863, 1751, 1678, 1630

NMR(CDCl₃, δ): 0.58(d, J=6.2 Hz, 3H), 0.68(d, J=6.4 Hz, 3H), 0.88(d,J=6.8 Hz, 3H), 0.92(d, J=6.8 Hz, 3H), 1.30-1.60(m, 3H), 1.92(m, 1H),2.26(s, 3H), 3.67(m, 1H), 4.32(m, 1H), 5.48(d, J=7.5 Hz, 1H), 5.99(d,J=5.0 Hz, 1H), 6.42(d, J=9.9 Hz, 1H), 7.45-7.65(m, 6H), 7.75-7.90(m, 4H)

EXAMPLE 83 Preparation of 2-[(1S,2S)-2-{(S)-2-(4-fluorophenylsulfonylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 245 in Table 1)

mp: 207°-208° C.(dec.)

IR(KBr, cm⁻¹): 3561, 3272, 1858, 1667, 1634

NMR(CD₃ OD, δ): 0.39(d, J=6.7 Hz, 3H), 0.46(d, J=6.5 Hz, 3H), 0.74(d,J=6.7 Hz, 3H), 0.86(m, 1H), 1.02(d, J=6.7 Hz, 3H), 1.03(m, 1H), 1.39(m,1H), 1.96(m, 1H), 3.72(dd, J=11 Hz, 4.2 Hz, 1H), 3.90(m, 1H), 5.14(d,J=2.4 Hz, 1H), 7.15-7.28(m, 2H), 7.50-7.65(m, 3H), 7.78-7.90(m, 2H),7.98-8.18(m, 2H), 8.09(d, J=9.6 Hz, 1H)

EXAMPLE 84 Preparation of 2-[(1S,2S)-2-{(S)-2-(2-chlorophenylsulfonylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 246 in Table 1)

mp: 106°-109° C.(dec.)

IR(KBr, cm⁻¹): 3327, 1856, 1624

NMR(CDCl₃, δ): 0.23(d, J=6.4 Hz, 3H), 0.53(d, J=6.5 Hz, 3H), 1.10(d,J=6.3 Hz, 3H), 1.12(d, J=6.3 Hz, 3H), 1.27(m, 2H), 1.41(m, 1H), 2.38(m,1H), 3.50(m, 1H), 3.93(m, 1H), 5.21(d, J=4.3 Hz, 1H), 7.01(d, J=6.2 Hz,1H), 7.31-7.42(m, 2H), 7.42-7.60(m, 5H), 8.01(dd, J=6.8 Hz, 1.4 Hz, 2H),8.03(d, J=7.3 Hz, 1H)

EXAMPLE 85 Preparation of 2-[(1S,2S)-2-{(S)-2-(4-chlorophenylsulfonylamino)-4-methylvalerylamino}-1hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 248 in Table 1)

mp: 206° C.(dec.)

IR(KBr, cm⁻¹): 3559, 3268, 1856, 1664, 1634

NMR(CD₃ OD, δ): 0.39(d, J=6.7 Hz, 3H), 0.48(d, J=6.5 Hz, 3H), 0.71(d,J=6.7 Hz, 3H), 0.82(m, 1H), 1.01(d, J=6.6 Hz, 3H), 1.05(m, 1H), 1.41(m,1H), 1.93(m, 1H), 3.74(dd, J=11 Hz, 4.1 Hz, 1H), 3.89(m, 1H), 5.13(d,J=2.4 Hz, 1H), 7.50-7.68(m, 5H), 7.75-7.83(m, 2H), 7.98-8.14(m, 3H)

EXAMPLE 86 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(4-trisulfonylamino)valerylamino}butyl]-3-phenylcyclopropenone(compd. No. 251 in Table 1)

mp: 203°-205° C.(dec.)

IR(KBr, cm⁻¹): 3318, 1856, 1680, 1626

NMR(CDCl₃, δ): 0.19(d, J=6.4 Hz, 3H), 0.49(d, J=6.4 Hz, 3H), 1.07(d,J=6.6 Hz, 3H), 1.12(d, J=6.6 Hz, 3H), 0.90-1.40(m, 3H), 2.25(m, 1H),2.38(s, 3H), 3.49(m, 1H), 4.01(m, 1H), 5.23(dd, J=7.8 Hz, 3.8 Hz, 1H),5.82(d, J=8.0 Hz, 1H), 7.13-7.35(m, 3H), 7.44-7.60(m, 4H), 7.73(d, J=8.2Hz, 2H), 8.0(d, J=6.4 Hz, 2H)

EXAMPLE 87 Preparation of 2-[(1S,2S)-1-hydroxy-2-{(S)-2-(4-methoxyphenylsulfonylamino)-4-methylvalerylamino}-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 257 in Table 1)

mp: 201°-202° C.(dec.)

IR(KBr, cm⁻¹): 3335, 1856, 1680, 1626

NMR(CDCl₃, δ): 0.23(d, J=6.4 Hz, 3H), 0.51(d, J=6.5 Hz, 3H), 1.08(d,J=6.8 Hz, 3H), 1.12(d, J=6.7 Hz, 3H), 0.93-1.37(m, 3H), 2.30(m, 1H),3.48(m, 1H), 3.83(s, 3H), 3.99(m, 1H), 5.22(dd, J=8.1 Hz, 3.8 Hz, 1H),5.81(d, J=7.6 Hz, 1H), 6.91(d, J=9.0 Hz, 2H), 7.03(d, J=6.3 Hz, 1H),7.42-7.61(m, 4H), 7.78(d, J=9.0 Hz, 2H), 7.95-8.08(m, 2H)

EXAMPLE 88 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(1-naphtylsulfonylamino)valerylamino}butyl]-3-phenylcyclopropenone(compd. No. 259 in Table 1)

mp: 109°-115° C.

IR(KBr, cm⁻¹): 3360, 1856, 1640, 1603

NMR(DMSO-d6, δ): -0.01(d, J=4.4 Hz, 3H), 0.12(d, J=6.3 Hz, 3H), 0.61(d,J=6.1 Hz, 3H), 0.89(d, J=6.6 Hz, 3H), 0.80-1.22(m, 3H), 1.79(m, 1H),3.58-3.78(m, 2H), 5.02(m, 1H), 6.24(d, J=4.7 Hz, 1H), 7.45-7.65(m, 6H),7.85-7.99(m, 3H), 7.99-8.07(m, 1H), 8.07-8.12(m, 3H), 8.59(d, J=9.1 Hz,1H),

EXAMPLE 89 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(2-naphtylsulfonylamino)valerylamino}butyl]-3-phenylcyclopropenone(compd. No. 260 in Table 1) mp: 214° C.(dec.)

IR(KBr, cm⁻¹): 3551, 3474, 3264, 1856, 1669, 1634

NMR(DMSO-d6 δ): 0.23-0.45(m, 9H), 0.75(d, J=6.2 Hz, 3H), 0.65-0.85(m,1H), 0.85-1.05(m, 1H), 1.34(m, 1H), 1.67(m, 1H), 3.64(m, 1H), 3.81(m,1H), 4.99(m, 1H), 6.24(m, 1H), 7.46-8.10(m, 13H), 8.33(m, 1H)

EXAMPLE 90 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(3-pyridylsulfonylamino)valerylamino}butyl]-3-phenylcyclopropenone (compd. No. 262 in Table 1)

mp: 110°-112° C.

IR(KBr, cm⁻¹): 3285, 1856, 1672, 1624

NMR(CDCl₃, δ): 0.13(d, J=6.4 Hz, 3H), 0.42(d, J=6.4 Hz, 3H), 0.87(m,1H), 1.11(d, J=6.4 Hz, 3H), 1.13(d, J=6.5 Hz, 3H), 1.24(m, 2H), 2.24(m,1H), 3.53(m, 1H), 4.15(m, 1H), 5.29(d, J=2.8 Hz, 1H), 5.76(s, 1H),7.38-7.55(m, 4H), 7.68(s, 1H), 8.01(dd, J=7.6 Hz, 1.4 Hz, 2H), 8.17(ddd,J=8.1 Hz, 1.7 Hz, 1.7 Hz, 1H), 8.48(d, J=7.0 Hz, 1H), 8.74(dd, J=4.8 Hz,1.5 Hz, 1H), 9.10(d, J=2.0 Hz, 1H)

EXAMPLE 91 Preparation of 2-[(1S,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(8-quinolylsulfonylamino)valerylamino}butyl]-3-phenylcyclopropenone(compd. No. 265 in Table 1)

mp: 132°-137° C.(dec.)

IR(KBr, cm⁻¹): 3287, 1856, 1665, 1626

NMR(CDCl₃, δ): -0.03(d, J=6.3 Hz, 3H), 0.41(d, J=6.4 Hz, 3H),0.90-1.30(m, 3H), 1.07(d, J=6.6 Hz, 3H), 0.83(d, J=6.7 Hz, 3H), 2.42(m,1H), 3.52(m, 1H), 3.79(m, 1H), 5.09(dd, J=7.8 Hz, 5.8 Hz, 1H), 5.70(d,J=7.8 Hz, 1H), 6.65(d, J=2.9 Hz, 1H), 7.35(d, J=8.4 Hz, 1H),7.40-7.70(m, 5H), 8.02(dd, J=7.4 Hz, 2.0 Hz, 2H), 8.09(dd, J=8.3 Hz, 1.3Hz, 1H), 8.27-8.39(m, 2H), 9.05(dd, J=4.3 Hz, 1.6 Hz, 1H)

EXAMPLE 92 Preparation of 2-[(1S, 2S)-2-((S)-2-benzyloxycarbonylamino-3-phenylpropionylamino)-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 276 in Table 1)

mp: 175°-177° C.

IR(KBr, cm⁻¹): 3300, 1850, 1697, 1648, 1620

NMR(CDCl₃, δ): 0.85(d, J=6.7 Hz, 3H), 0.95(d, J=6.6 Hz, 3H), 2.28(m,1H), 2.80(dd, J=14 Hz, 7.9 Hz, 1H), 2.99(dd, J=14 Hz, 5.9 Hz, 1H),3.60(m, 1H), 4.42(m, 1H), 4.85-5.05(m, 3H), 5.42(d, J=6.2 Hz, 1H),5.99(d, J=8.0 Hz, 1H), 7.05-7.35(m, 10H), 7.35-7.60(m, 4H), 7.92-8.03(m,2H)

EXAMPLE 93 Preparation of2-[(2S)-2-((S)-2-benzyloxycarbonylamino-3-phenylpropionylamino)-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 276 in Table 1)

IR(KBr, cm⁻¹): 3300, 1855, 1693, 1645, 1620

NMR(CDCl₃, δ): 0.84(d, J=6.2 Hz, 1.8H), 0.95(d, J=6.7 Hz, 1.2H), 1.02(d,J=6.4 Hz, 1.8H), 1.05(d, J=6.0 Hz, 1.2H), 2.03(m, 0.4H), 2.27(m, 0.6H),2.75-2.88(m, 0.6H), 2.90-3.05(m, 1.4H), 3.58(m, 0.6H), 4.05(m, 0.4H),4.41(q, J=6.8 Hz, 1H), 4.73(m, 0.4H), 4.85-5.05(m, 3.6H), 5.27-5.45(m,1H), 5.94(d, J=7.9 Hz, 0.6H), 7.70(d, J=7.6 Hz, 0.4H), 7.05-7.37(m,10H), 7.44-7.62(m, 3H), 7.95-8.05(m, 2H)

EXAMPLE 94 Preparation of2-[(2S)-2-((S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino)-1-hydroxyhexyl]-3-phenylcyclopropenone(compd. No. 280 in Table 1)

IR(KBr, cm⁻¹): 3310, 1855, 1790, 1755, 1725

NMR(CDCl₃, δ): 0.65-0.75(m, 1.2H), 0.75-1.05(m, 7.8H), 1.10-2.0(m, 20H),2.07(s, 1H), 3.65-3.90(m, 2H), 4.0-4.20(m, 1.7H), 4.20-4.35(m, 0.3H),4.95-5.05(m, 1H), 5.10.5.30(m, 0.3H), 5.45-5.60(m, 0.7H), 5.70-5.85(m,1H), 7.0-7.25(m, 0.7H), 7.45-7.56(m, 3.3H), 7.95-8.05(m, 2H)

EXAMPLE 95 Preparation of2-[(2S)-2-((S)-2-benzyloxycarbonylamino-4-methylvalerylamino]-1-hydroxyhexyl]-3-phenylcyclopropenone(compd. No. 281 in Table 1)

IR(KBr, cm⁻¹): 3320, 1855, 1700, 1655, 1625

NMR(CDCl₃, δ): 0.60-0.70(m, 1.8H), 0.70-1.0(m, 7.2H), 1.20-1.65(m, 8H),1.75-1.95(m, 1H), 2.0(s, 1H), 4.0-4.30(m, 2H), 4.90-5.10(m, 2.7H),5.35(d, J=7 Hz, 0.3H), 5.70-5.85(m, 1H), 7.05-7.10(m, 0.7H), 7.30(s,5H), 7.45-7.56(m, 3.3H), 7.95-8.10(m, 2H)

EXAMPLE 96 Preparation of2-[(2S)-1-hydroxy-2-{(S)-4-methyl-(2-pyridylmethoxycarbonylamino)valerylamino]hexyl]-3-phenylcyclopropenone(compd. No. 282 in Table 1)

IR(KBr, cm⁻¹): 3320, 1855, 1715, 1655, 1628

NMR(CDCl₃, δ): 0.65-0.75(m, 1.8H), 0.75-0.95(m, 7.2H), 1.10-1.70(m, 8H),1.70-2.0(m, 1H), 2.28(s, 1H), 4.05-4.35(m, 2H), 5.03(s, 1H), 5.16(s,2H), 6.13(d, J=8 Hz, 1H), 7.13-7.25(m, 1H), 7.31(d, J=7 Hz, 1H),7.35-7.60(m, 4H), 7.66(t, J=7 Hz, 1H), 7.95-8.05(m, 2H), 8.51(d, J=5 Hz,1H)

EXAMPLE 97 Preparation of2-[(RS)-2-((S)-2-tert-butoxycarbonylamino-4-methylvalerylamino)-1-hydroxy-2-methylpropyl]-3-phenylcyclopropenone (compd. No. 290 in Table 1)

IR(KBr, cm⁻¹): 3320, 1858, 1690, 1650, 1625

NMR(CDCl₃, δ): 0.60-0.95(m, 6H), 1.10-1.70(m, 18H), 3.92(m, 1H),4.65-4.92(m, 2H), 6.63(d, J=13 Hz, 1H), 6.70-6.95(m, 1H), 7.20-7.45(m,3H), 8.01(d, J=6.5 Hz, 2H)

EXAMPLE 98 Preparation of2-[(RS)-2-((S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino)-1-hydroxy-2-methylpropyl]-3-phenylcyclopropenone(compd. No. 289 in Table 1)

IR(KBr, cm⁻¹): 3300, 1857, 1695, 1648, 1623

NMR(CDCl₃, δ): 0.65-1.05(m, 8H), 1.05-1.90(m, 18H), 3.68-3.95(m, 2H),4.0(m, 1H), 4.70-4.88(m, 1H), 4.99(m, 1H), 6.50-6.93(m, 2H),7.40-7.60(m, 3H), 8.01(dd, J=5.8 Hz, 1.8 Hz, 2H)

EXAMPLE 99 Preparation of2-[(RS)-2-((S)-2-amino-4-methylvalerylamino)-1-hydroxy-2-methylpropyl]-3-phenylcyclopropenonehydrochloride (compd. No. 294 in Table 1)

IR(KBr, cm⁻¹): 3250, 1857, 1678, 1615

NMR(CD₃ OD, δ): 0.90-1.10(m, 6H), 1.29(s, 1.5H), 1.46(s, 1.5H), 1.51(s,1.5H), 1.57(s, 1.5H), 1.55-1.85(m, 3H), 3.89(m, 1H), 5.42(s, 0.5H),5.76(s, 0.5H), 7.55-7.75(m, 3H), 8.0-8.10(m, 2H)

EXAMPLE 100 Preparation of2-[(RS)-1-hydroxy-2-methyl-2-((S)-4-methyl-2-phenylsulfonylaminovalerylamino)propyl]-3-phenylcyclopropenone(compd. No. 297 in Table 1)

IR(KBr, cm⁻¹): 3350, 3290, 3180, 1858, 1654, 1623, 1615

NMR(CDCl₃, δ): 0.41(d, J=6.4 Hz, 1.5H), 0.52(d, J=6.5 Hz, 1.5H), 0.56(d,J=6.6 Hz, 1.5H), 0.66(d, J=6.5 Hz, 1.5H), 1.08-1.38(m, 3H),1.34(s,1.5H), 1.39(s, 1.5H), 1.49(s, 1.5H), 1.51(s, 1.5H), 3.65(m, 1H),4.67(d, J=10 Hz, 0.5H), 4.90(d, J=8.4Hz, 0.5H), 5.73(d, J=8.2 Hz, 0.5H),6.27(d, J=8.4 Hz, 0.5H, 6.53(d, J=7.6 Hz, 0.5H), 6.90(s, 0.5H), 6.98(d,J=10 Hz, 0.5H), 7.26(s, 0.5H, 7.45-7.65(m, 6H), 7.84(t, J=6.7 Hz, 2H),8.00(d, J=7.1 Hz, 2H)

EXAMPLE 101 Preparation of2-[(RS)-1-hydroxy-2-methyl-2-{(S)-4-methyl-2-(N-(methylthiomethyl)phenylsulfonylamino)valerylamino}propyl]-3-phenylcyclopropenone (compd. No. 298 in Table 1)

IR(KBr, cm⁻¹): 3350, 3280, 1856, 1670, 1624

NMR(CDCl₃, δ): 0.33(d, J=6.3 Hz, 1.5H), 0.38(d, J=6.3 Hz, 1.5H), 0.48(d,J=6.4 Hz, 1.5H), 0.54(d, J=6.5 Hz, 1.5H), 0.65-1.15(m, 3H), 1.51(s,1.5H), 1.59(s, 1.5H), 1.62(s, 1.5H), 1.71(s, 1.5H), 2.27(s, 1.5H),2.28(s, 1.5H), 3.92(m, 0.5H), 3.95(m, 0.5H), 4.23(d, J=15 Hz, 0.5H),4.33(d, J=15 Hz, 0.5H), 4.61(d, J=15 Hz, 0.5H), 4.70(d, J=15 Hz, 0.5H),4.82(d, J=9.4 Hz, 0.5H), 5.05(d, J=7.8 Hz, 0.5H), 6.28(d, J=7.9 Hz,0.5H), 6.70(d, J=9.5 Hz, 0.5H), 6.73(s, 0.5H), 7.18(s, 0.5H),7.45-7.70(m, 6H), 7.80-7.92(m, 2H), 7.99-8.12(m, 2H)

EXAMPLE 105 Preparation of2-[2-((S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino)-2-methylpropionyl]-3-phenylcyclopropenone(compd. No. 299 in Table 1)

mp: 42°-49° C.

IR(KBr, cm⁻¹): 3350, 1768, 1720, 1680

NMR(CDCl₃, δ): 0.85-1.35(m, 14H), 1.50(s, 3H), 1.50-1.87(m, 9H), 3.91(m,2H), 4.52(m, 1H), 4.58-4.63(m, 1H), 5.09(m, 1H), 7.30-7.55(m, 3H),7.93-8.06(m, 2H)

EXAMPLE 103 Preparation of2-[2-methyl-2-((S)-4-methyl-2-phenylsulfonylaminovalerylamino)propionyl]-3-phenylcyclopropenone(compd. No. 301 in Table 1)

mp: 53°-59° C.

IR(KBr, cm⁻¹): 3430, 3260, 1765, 1678

NMR(CDCl₃, δ): 0.60(s, 2H), 0.79(s, 1H), 0.95(d, J=6.4 Hz, 3H), 0.97(d,J=5.1 Hz, 3H), 1.23(s, 1H), 1.35(s, 2H), 1.60(m, 2H), 1.85(m, 1H),3.86(s, 0.3H), 4.11(m, 1H), 4.15(s, 0.7H), 5.24(m, 1H), 7.33-7.62(m,7H), 7.80-7.95(m, 4H)

EXAMPLE 104 Preparation of 2-[(1S,2S)-2-((S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]-3-(4-fluorophenyl)cyclopropenone(compd. No. 311 in Table 1)

mp: 86°-90° C.

IR(KBr, cm⁻¹): 3320, 1858, 1693, 1656, 1625, 1602

NMR(CDCl₃, δ): 0.79(d, J=5.9 Hz, 6H), 1.01(d, J=6.6 Hz, 3H), 1.09(d,J=6.6 Hz, 3H), 0.70-1.45(m, 7H), 1.45-1.83(m, 7H), 2.39(m, 1H),3.50-3.85(m, 3H), 4.08(m, 1H), 5.10(dd, J=8.6 Hz, 4.7 Hz, 1H), 5.25(m,1H), 6.23(m, 1H), 7.19(dd, J=8.5 Hz, 8.5 Hz, 2H), 7.47(m, 1H), 8.01(dd,J=8.5 Hz, 5.5 Hz, 2H)

EXAMPLE 105 Preparation of 2-[(1S,2S)-2-((S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]-3-(4-fluorophenyl)cyclopropenone(compd. No. 311 in Table 1)

mp: 166°-168° C.

IR(KBr, cm⁻¹): 3340, 3260, 1861, 1714, 1655, 1625

NMR(CDCl₃, δ): 0.63-1.03(m, 8H), 1.07(d, J=6.6 Hz, 3H), 1.14(d, J=6.6Hz, 3H), 1.03-1.80(m, 12H), 2.14(m, 1H), 3.55-3.85(m, 2H), 3.95-4.15(m,2H), 5.0-5.23(m, 2H), 5.29(d, J=5.7 Hz, 1H), 6.90(d, J=7.0 Hz, 1H),7.18(dd, J=8.5 Hz, 8.5 Hz, 2H), 8.04(dd, J=8.5 Hz, 5.8 Hz, 2H)

EXAMPLE 106 Preparation of 2-[(1S,2S)-2-((S)-2-tert-butoxycarbonylamino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]-3-(4-fluorophenyl)cyclopropenone(compd. No. 312 in Table 1)

mp: 90°-96° C.

IR(KBr, cm⁻¹): 3340, 1858, 1687, 1655, 1635, 1600

NMR(CDCl₃, δ): 0.77(d, J=6.3 Hz, 6H), 1.02(d, J=6.6 Hz, 3H), 1.09(d,J=6.4 Hz, 3H), 1.20-1.65(m, 3H), 1.39(s, 9H), 2.40(m, 1H), 3.68(m, 1H),4.07(m, 1H), 5.03-5.31(m, 2H 6.23(m, 1H), 7.10-7.25(m, 3H), 7.95-8.13(m,2H)

EXAMPLE 107 Preparation of 2-[(1R,2S)-2-((S)-2-tert-butoxycarbonylamino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]-3-(4-fluorophenyl)cyclopropenone(compd. No. 312 in Table 1)

IR(KBr, cm⁻¹): 3320, 1859, 1686, 1627

NMR(CDCl₃, δ): 0.71(d, J=5.7 Hz, 6H), 1.08(d, J=6.6 Hz, 3H), 1.14(d,J=6.7 Hz, 3H), 1.20-1.70(m, 3H), 1.37(s, 9H), 2.14(m, 1H), 3.98-4.15(m,2H), 4.98(m, 1H), 5.13(m, 1H), 5.39(d, J=5.8 Hz, 1H), 6.88(d, J=6.9 Hz,1H), 7.17(dd, J=8.6 Hz, 8.6 Hz, 2H), 8.03(dd, J=8.6 Hz, 5.5 Hz, 2H)

EXAMPLE 108 Preparation of 2-[(1s,2S)-2-((S)-2-amino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]-3-(4-fluorophenyl)cyclopropenonehydrochloride (compd. No. 314 in Table 1)

mp: 141°-145° C.(dec.)

IR(KBr, cm⁻¹): 3250, 1857, 1683, 1620, 1600

NMR(CD₃ OD, δ): 0.52(d, J=6.5 Hz, 3H), 0.74(d, J=6.5 Hz, 3H), 1.02(d,J=6.8 Hz, 3H), 1.13(d, J=6.6 Hz, 3H), 1.0-1.35(m, 2H), 1.43(m, 1H),2.11(m, 1H), 3.81(m, 1H), 4.11(m, 1H), 5.23(d, J=2.1 Hz, 1H),7.18-7.42(m, 2H), 8.10-8.25(m, 2H)

EXAMPLE 109 Preparation of 2-[(1R,2S)-2-((S)-2-amino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]-3-(4-fluorophenyl)cyclopropenonehydrochloride (compd. No. 314 in Table 1)

IR(KBr, cm⁻¹): 3300, 3250, 1860, 1683, 1620, 1603

NMR(CD₃ OD, δ): 0.84(d, J=5.9 Hz, 3H), 0.88(d, J=5.9 Hz, 3H), 1.04(d,J=6.8 Hz, 3H), 1.10(d, J=6.8 Hz, 3H), 1.58-1.78(m, 3H), 2.16(m, 1H),3.84(m, 1H), 4.02(m, 1H), 5.17(d, J=6.7 Hz, 1H), 7.22-7.35(m, 2H),8.05-8.16(m, 2H)

EXAMPLE 110 Preparation of 2-(4-fluorophenyl)-3-[(1R,2S)-1-hydroxy-3-methyl-2-{(S)-4-methyl-2-(phenoxyacetylamino)valerylamino}butyl]cyclopropenone (compd. No. 315 in Table 1)

mp: 75°-79° C.

IR(KBr, cm⁻¹): 3410, 3290, 1853, 1650, 1620

NMR(CDCl₃, δ): 0.66(d, J=6.2 Hz, 6H), 1.05(d, J=6.6 Hz, 3H), 1.14(d,J=6.7 Hz, 3H), 1.36(m, 2H), 1.56(m, 1H), 2.14(m, 1H), 4.02(m, 1H),4.41(d, J=15 Hz, 1H), 4.48(d, J=15 Hz, 1H), 4.51(m, 1H), 5.13(dd, J=6.4Hz, 2.5 Hz, 1H), 5.29(d, J=6.4 Hz, 1H), 6.91(d, J=7.9 Hz, 2H), 7.03(t,J=7.4 Hz, 1H), 7.12-7.28(m, 3H), 7.31(dd, J=8.5 Hz, 7.5 Hz, 2H),8.04(dd, J=8.7 Hz, 5.5 Hz, 2H)

EXAMPLE 111 Preparation of 2-(4-fluorophenyl)-3-[(1S,2S)-1-hydroxy-3-methyl-2-((S)-4-methyl-2-phenylsulfonylaminovalerylamino)butyl]cyclopropenone(compd. No. 317 in Table 1)

mp: 211°-212° C.(dec.)

IR(KBr, cm⁻¹): 3400, 3300, 1853, 1670, 1619

NMR(CDCl₃, δ): 0.16(d, J=6.4 Hz, 3H), 0.48(d, J=6.4 Hz, 3H), 0.93(m,1H), 1.10(d, J=6.7 Hz, 3H), 1.13(d, J=6.7 Hz, 3H), 1.15-1.35(m, 2H),2.29(m, 1H), 3.47(m, 1H), 4.10(m, 1H), 5.26(dd, J=7.9 Hz, 5.3 Hz, 1H),5.76(d, J=7.3 Hz, 1H), 7.17(dd, J=8.6 Hz, 8.6 Hz, 2H), 7.38-7.57(m, 4H),7.54(d, J=7.4 Hz, 1H), 7.86(d, J=6.7 Hz, 2H), 8.04(dd, J=8.6 Hz, 5.5 Hz,2H)

EXAMPLE 112 Preparation of2[(2S)-2-((S)-2-benzyloxycarbonylamino-4-methylvalerylamino)-1-hydroxyhexyl]-3-(4-fluorophenyl)cyclopropenone(compd. No. 319 in Table 1)

IR(KBr, cm⁻¹): 3310, 1857, 1698, 1652, 1625, 1600 NMR(CDCl₃, δ):0.75-0.98(m, 9H), 1.15-1.95(m, 9H), 3.95-4.30(m, 2H), 4.88-5.12(m, 3H),5.39(d, J=7.8 Hz, 0.3H), 5.70-5.90(m, 1.7H), 7.08-7.35(m, 3H), 7.30(s,5H), 7.90-8.10(m, 2H)

EXAMPLE 113 Preparation of2-[(2S)-2-((S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino)-1-hydroxyhexyl]-3-(2-tolyl)cyclopropenone(compd. No. 328 in Table 1)

IR(KBr, cm⁻¹): 3320, 1845, 1692, 1655, 1615

NMR(CDCl₃ δ): 0.60-1.05(m, 11H), 1.05-2.0(m, 18H), 2.66(s, 2.1H),2.68(s, 0.9H), 3.65-3.95(m, 2H), 3.95-4.35(m, 2H), 4.95-5.12(m, 1H),5.24(m, 0.3H), 5.55(m, 0.7H), 7.05-7.35(m, 6H), 7.35-7.50(m, 3H),8.05-8.20(m, 2H)

EXAMPLE 114 Preparation of2-[(2S)-2-((S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino)-1-hydroxy-1-hexyl]-3-(5-trimethylsilyl-2-furil)cyclopropenone(compd. No. 376 in Table 1)

IR(KBr, cm⁻¹): 3310, 1865, 1695, 1655, 1623

NMR(CDCl₃, δ): 0.35(s, 9H), 0.70-1.05(m, 11H), 1.05-2.0(m, 18H),3.70-3.95(m, 2H), 3.95-4.35(m, 2H), 4.92(m, 1H), 5.0-5.50(m, 1H),6.45-6.85(m, 1)n6.76(d, J=3.4 Hz, 1H), 7.20-7.28(m, 1H)

EXAMPLE 115 Preparation of2-[(2S)-2-((S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino)-1-hydroxy-1-hexyl]-3-(5-trimethylsilyl-2-thienyl)cyclopropenone(compd. No. 387 in Table 1)

IR(KBr, cm⁻¹): 3320, 1853, 1695, 1655, 1615

NMR(CDCl₃, δ): 0.35(s, 9H), 0.70-1.05(m, 11H), 1.10-2.0(m, 18H),3.73-3.90(m, 2H), 3.90-4.15(m, 2H), 4.92(d, J=4.8 Hz, 1H), 4.95-5.10(m,0.3H), 5.10-5.30(m, 0.7H), 6.50-6.65(m, 0.3H), 6.80-6.95(m, 0.7H),7.29(d, J=3.6 Hz, 1H), 7.82(d, J=3.6 Hz, 0.7H), 7.84(d, J=3.6 Hz, 0.3H)

EXAMPLE 116 Preparation of2-[(2S)-2-((S)-2-benzyloxycarbonylamino-4-methylvalerylamino)-3-methylbutyl]-3-(1-hydroxy-1-methylethyl)cyclopropenone(compd. No. 422 in Table 1)

IR(KBr, cm⁻¹): 3316, 1840, 1696, 1655

NMR(CD₃ OD, δ): 0.80-1.0(m, 9.9H)n1.03(d, J=6.6 Hz, 2.1H), 1.49(s,2.1H), 1.52(s, 1.8H), 1.53(s, 2.1H), 1.40-1.80(m, 3H), 1.86-2.20(m, 1H),4.02(m, 1H), 4.18(m, 1H), 5.03(d,

J=2.2 Hz,1H), 5.08(s, 2H), 7.18-7.41(m, 5H), 7.82(d, J=8.3 Hz, 0.3H),7.98(d, J=8.7 Hz, 0.7H)

EXAMPLE 117 Preparation of2-[(2S)-2-((S)-2-benzyloxycarbonylamino-4-methylvalerylamino)-1-hydroxy-3-methylbutyl]-3-(1-hydroxy-1-phenylmethyl)cyclopropenone(compd. No. 444 in Table 1)

IR(KBr, cm⁻¹): 3399, 1846, 1696, 1647

NMR(CD₃ OD, δ): 0.85-1.10(m, 12H), 1.30-1.75(m, 3H), 1.85-2.10(m, 1H),3.85-4.23(m, 2H), 4.94(m, 0.3H), 5.03(m, 0.7H), 5.08(s, 2H),5.75-5.90(m, 1H), 7.13-7.55(m, 10H)

EXAMPLE 118 Preparation of 2-[(1S,2S)-2-{(S)-2-((S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 467 in Table 2)

mp: 190°-192° C.

IR(KBr, cm⁻¹): 3310, 1848, 1687, 1638, 1625

NMR(CDCl₃, δ): 0.77(d, J=4.9 Hz, 6H), 0.91(d, J=5.4 Hz, 3H), 0.94(d,J=6.1 Hz, 3H), 1.01(d, J=6.5 Hz, 3H), 1.08(d, J=6.5 Hz, 3H),0.80-1.85(m, 17H), 2.37(m, 1H), 3.62(m, 1H), 3.75-4.0(m, 3H), 4.08(m,1H), 4.42(m, 1H), 5.10(s, 1H), 5.28(m, 1H), 6.12(m, 1H), 6.88(d, J=7.5Hz, 1H), 7.45-7.85(m, 4H), 7.98(d, J=7.1 Hz, 2H)

EXAMPLE 119 Preparation of 2-[(1R,2S)-2-{(S)-2-((S)-2-cyclohexylmethoxycarbonylamino-4-methylvalerylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone(compd. No. 467 in Table 2)

mp: 109°-116° C.

IR(KBr, cm⁻¹): 3300, 1858, 1699, 1645

NMR(CDCl₃, δ): 0.52(d, J=5.6 Hz, 3H), 0.59(d, J=5.6 Hz, 3H), 0.85(d,J=6.4 Hz, 3H), 0.89(d, J=6.4 Hz, 3H), 0.80-1.0(m, 2H), 1.01(d, J=6.4 Hz,3H), 1.13(d, J=6.5 Hz, 3H), 1.05-1.40(m, 4H), 1.40-1.85(m, 11H), 2.20(m,1H), 3.70-3.93(m, 2H), 3.98-4.10(m, 2H), 4.52(m, 1H), 5.15(m, 1H),5.39(s, 1H), 5.85(d, J=6.5 Hz, 1H), 7.01(d, J=6.8 Hz, 1H), 7.35-7.65(m,4H), 8.01(d, J=6.9 Hz, 2H)

EXAMPLE 120 Preparation of 2-[(1S,2S)-2-{(S)-2-((S)-2-benzyloxycarbonylamino-3-phenylpropionylamino)-4-methylvalerylamino}-1-hydroxy-3-methylbutyl]-3-phenylcyclopropenone (compd. No. 478 in Table2)

mp: 128°-130° C.

IR(KBr, cm⁻¹): 3297, 1856, 1703, 1649, 1615

NMR(CDCl₃, δ): 0.69(d, J=6.0 Hz, 3H), 0.74(d, J=5.8 Hz, 3H), 1.02(d,J=6.5 Hz, 3H), 1.09(d, J=6.5 Hz, 3H), 1.25-1.50(m, 3H), 2.42(m, 1H),2.95-3.10(m, 2H), 3.49(m, 1H), 4.33-4.53(m, 2H), 4.95-5.15(m, 3H),5.35(m, 1H), 6.25(d, J=8.9 Hz, 1H), 6.84(m, 1H), 7.08-7.19(m, 2H),7.19-7.38(m, 8H), 7.40-7.60(m, 3H), 7.64(d, J=7.1 Hz, 1H), 7.96(dd,J=7.7 Hz, 1.7 Hz, 2H)

The following experiments were conducted to evaluate the biologicalactivity of compound (I) prepared in the above Examples.

EXPERIMENT 1 Assay of Thiol Protease Inhibitory Activity

Inhibitory activity against papain (P-3125, Sigma) and cathepsin B(C-6286, Sigma) was assayed according to the method described in aliterature [Biochemical Journal, 201, 189 (1982)]. Capthesin L waspurified from rat kidney according to the method in a literature[Journal of Biochemistry, 100, 35 (1986)], and the inhibitory activityagainst it was assayed in the same manner as described in the aboveliterature for cathepsin B. Further, m-calpain was purified from ratbrain according to a known method [Journal of Biological Chemistry, 254,p.3210 (1984)] and the inhibitory activity against it was assayed by amethod described in a literature [Journal of Biological Chemistry, 259,12489 (1984)]. The results are showing in Tables 3 and 4. It is evidentfrom Tables 3 and 4 that the compounds in the present invention have apotent inhibitory activity against thiol proteases such as papain,cathepsin B, cathepsin L, m-calpain or the like.

                  TABLE 3                                                         ______________________________________                                        Compd. of Ex. No.                                                                         IC.sub.50 (μM)                                                 (Compd.               cathepsin                                                                              cathepsin                                      No. in Table 1)                                                                           papain    B        L      m-calpain                               ______________________________________                                        1 (No. 77)  0.054     0.71      0.00086                                                                             1.6                                     2 (No. 77)  22        0.044    0.0012 3.3                                     4 (No. 4)   5.8       0.41     --     0.50                                    5 (No. 10)  >100      3.0      0.75   2.3                                     6 (No. 15)  0.076     0.16     0.54   0.81                                    7 (No. 16)  0.14      0.32     0.24   2.4                                     25 (No. 83) 13        32       5.7    2.1                                     26 (No. 83) 4.2       43       5.8    1.6                                     94 (No. 280)                                                                              0.074     1.0      0.062  2.7                                     95 (No. 281)                                                                              13        11       1.27   3.0                                     96 (No. 282)                                                                              7.0       28       4.60   5.7                                     114 (No. 376)                                                                             0.68      2.5      0.58   5.6                                     115 (No. 387)                                                                             0.48      1.5      0.27   11                                      ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        (Inhibitory activity against m-calpain                                        Compd. of Ex. No.   IC.sub.50                                                 (Compd. No. in Table 1, 2)                                                                        (μM)                                                   ______________________________________                                        9 (No. 26)          5.0                                                       20 (No. 72)         1.3                                                       21 (No. 72)         3.0                                                       29 (No. 97)         1.7                                                       31 (No. 99)         1.3                                                       32 (No. 99)         1.2                                                       33 (No. 102)        0.84                                                      37 (No. 114)        2.1                                                       38 (No. 120)        4.0                                                       39 (No. 124)        1.9                                                       40 (No. 129)        2.6                                                       41 (No. 132)        1.4                                                       42 (No. 133)        1.5                                                       43 (No. 134)        1.7                                                       44 (No. 137)        3.0                                                       45 (No. 140)        1.0                                                       48 (No. 148)        0.63                                                      50 (No. 152)        1.2                                                       51 (No. 154)        0.75                                                      52 (No. 155)        0.74                                                      53 (No. 161)        2.3                                                       54 (No. 166)        1.1                                                       55 (No. 167)        0.80                                                      56 (No. 168)        2.2                                                       57 (No. 170)        3.1                                                       59 (No. 175)        1.6                                                       60 (No. 178)        1.1                                                       62 (No. 180)        1.4                                                       63 (No. 184)        1.6                                                       65 (No. 191)        1.8                                                       67 (No. 197)        0.88                                                      68 (No. 200)        3.1                                                       69 (No. 203)        3.0                                                       71 (No. 209)        1.3                                                       72 (No. 213)        0.40                                                      73 (No. 216)        1.4                                                       74 (No. 219)        0.80                                                      75 (No. 225)        3.3                                                       76 (No. 227)        4.6                                                       77 (No. 232)        0.95                                                      78 (No. 237)        0.44                                                      79 (No. 237)        1.8                                                       80 (No. 239)        0.35                                                      81 (No. 239)        4.3                                                       83 (No. 245)        3.0                                                       84 (No. 246)        0.85                                                      85 (No. 248)        0.84                                                      86 (No. 251)        0.75                                                      87 (No. 257)        1.0                                                       88 (No. 259)        0.65                                                      89 (No. 260)        0.46                                                      91 (No. 265)        1.9                                                       105 (No. 311)       1.5                                                       111 (No. 317)       2.9                                                       112 (No. 319)       4.3                                                       118 (No. 467)       0.84                                                      120 (No. 478)       1.2                                                       ______________________________________                                    

EXPERIMENT 2 Acute Toxicity

A suspension of the compound in the present invention in 0.5% CMC-Naaqueous solution was orally administered to SD female and male rats, andthe rats were observed for 7 days. The LD₅₀ value of the compound (I)prepared in Example 1 is: >2,000 mg/kg.

The following formulation examples are illustrative only.

Formulation 1

(1) Tablet

The following ingredients were admixed in a conventional manner andcompressed on customary tablet machine.

    ______________________________________                                        Compound in Example 1                                                                            30 mg                                                      Crystalline cellulose                                                                            60 mg                                                      Corn starch        100 mg                                                     Lactose            200 mg                                                     Magnesium stearate  4 mg                                                      ______________________________________                                    

(2) Soft gelatin capsule

The following ingredients were admixed in a conventional manner andfilled in soft capsules.

    ______________________________________                                        Compound in Example 1                                                                            30 mg                                                      Olive oil          300 mg                                                     Lecithin           20 mg                                                      ______________________________________                                    

(3) Injection

The following ingredients were admixed in a conventional manner andfilled in an ampoule in a volume of 1 ml.

    ______________________________________                                        Compound in Example 29                                                                            2.5 mg                                                    Sodium chloride     3.5 mg                                                    Distilled water for injection                                                                      1 ml                                                     ______________________________________                                    

What we claim is:
 1. A cyclopropenone derivative of general formula (I):##STR1000## wherein R¹ is hydrogen, R¹² --CO--, R¹² --O--CO--, R¹²--NH--CO-- or R¹² --SO₂ --(in which R¹² is C₁ -C₂₀ alkyl optionallysubstituted by one or more substituents selected from the consisting ofC₃ -C₁₅ cycloalkyl group, optionally substituted C₆ -C₁₄ aryl,optionally substituted C₃ -C₁₅ cycloalkyloxy, optionally substituted C₆-C₁₄ aryloxy, optionally substituted C₆ -C₁₄ arylthio, optionallysubstituted C₆ -C₁₄ arylsulfonyl, optionally substituted C₇ -C₂₀aralkyloxy, optionally substituted heterocyclic, oxo, hydroxyl, C₁ -C₁₀alkoxycarbonyl and carboxyl; C₃ -C₁₅ cycloalkyl; optionally substitutedC₆ -C₁₄ aryl or optionally substituted heterocyclic; R², R⁴ and R⁶ eachis independently hydrogen or C₁ -C₁₀ alkyl optionally substituted by C₁-C₅ alkoxy or by C₁ -C₅ alkylthio; R³, R⁵ and R⁷ each is independentlyhydrogen, C₁ -C₂₀ alkyl optionally substituted by C₃ -C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl or optionally substituted C₇ -C₂₀ aralkyl; R⁸ ishydrogen or C₁ -C₂₀ alkyl; R⁷ and R⁸ taken together may form C₃ -C₁₅cycloalkyl; R⁹ is hydroxy or C₂ -C₂₀ acyloxy; R¹⁰ is hydrogen; or R⁹ andR¹⁰ taken together may form oxo; R¹¹ is hydrogen, C₁ -C₂₀ alkyloptionally substituted by C₃ -C₁₅ cycloalkyl, C₃ -C₁₅ cycloalkyl, C₂-C₂₀ alkenyl, optionally substituted C₆ -C₁₄ aryl, optionallysubstituted C₇ -C₂₀ aralkyl, optionally substituted heterocyclic or--C(R¹³)(R¹⁴)--OH (in which R¹³ and R¹⁴ each is independently hydrogen,C₁ -C₂₀ alkyl, optionally substituted C₇ -C₂₀ aralkyl or optionallysubstituted C₆ -C₁₄ aryl, or R¹³ and R¹⁴ taken together may form C₃ -C₁₅cycloalkyl); and n is 0 or 1 or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1, wherein R¹ is hydrogen, R¹² --CO--,R¹² --O--CO--, R.sup. --NH--CO-- or R¹² --SO₂ -- (in which R¹² is C₁-C₂₀ alkyl optionally substituted by one or more substituents selectedfrom the consisting of C₃ -C₁₅ cycloalkyl, optionally substituted C₆-C₁₄ aryl group, optionally substituted C₆ -C₁₄ aryloxy, optionallysubstituted C₆ -C₁₄ arylthio, optionally substituted C₇ - C₂₀aralkyloxy, optionally substituted heterocyclic, oxo, hydroxy, C₁ -C₁₀alkoxycarbonyl and carboxyl; C₃ -C₁₅ cycloalkyl; optionally substitutedC₆ -C₁₄ aryl or optionally substituted heterocyclic; R², R⁴ and R⁶ eachis independently hydrogen atom or C₁ -C₁₀ alkyl optionally substitutedby C₁ -C₅ alkylthio; R³, R⁵ and R⁷ each is independently hydrogen, C₁-C₂₀ alkyl optionally substituted by C₃ -C₁₀ cycloalkyl, C₃ -C₁₀cycloalkyl or optionally substituted C₇ -C₂₀ aralkyl; R⁸ is hydrogenatom or C₁ -C₂₀ alkyl; and R¹¹ is hydrogen, C₁ -C₂₀ alkyl optionallysubstituted by C₃ -C₁₅ cycloalkyl, C₃ -C₁₅ cycloalkyl, C₂ -C₂₀ alkenyl,optionally substituted C₆ -C₁₄ aryl, C₇ -C₂₀ aralkyl, optionallysubstituted heterocyclic or --C(R¹³)(R¹⁴)--OH (in which R¹³ and R¹⁴ eachis independently hydrogen, C₁ -C₂₀ alkyl or C₆ -C₁₄ aryl).
 3. Thecompound of claim 2, wherein R¹ is R¹² --CO--, R¹² --O--CO--, R¹²--NH--CO-- or R¹² --SO₂ -- (in which R¹² is C₁ -C₁₅ alkyl optionallysubstituted by one or more substituents selected form the groupconsisting of C₃ -C₁₀ cycloalkyl; optionally substituted C₆ -C₁₄ aryloptionally substituted C₆ -C₁₄ aryloxy, optionally substituted C₆ -C₁ 4arylthio, optionally substituted C₇ -C₂₀ aralkyloxy, optionallysubstituted heterocyclic and oxo; C₃ -C₁₀ cycloalkyl; C₆ -C₁₄ aryl oroptionally substituted heterocyclic); R², R⁴ and R⁶ each isindependently hydrogen or C₁ -C₁₀ alkyl; R³, R⁵ and R⁷ each isindependently hydrogen, C₁ -C₁₅ alkyl optionally substituted by C₃ -C₁₀cycloalkyl, C₃ -C₁₀ cycloalkyl or optionally substituted C₇ -C₂₀aralkyl; R⁸ is hydrogen; R⁹ is hydroxy or C₂ -C₁₀ acyloxy; R¹⁰ ishydrogen; and R¹¹ is hydrogen, C₁ -C₁₅ alkyl optionally substituted byC₃ -C₁₀ cycloalkyl, C₃ -C₁₀ cycloalkyl, C₇ -C₂₀ aralkyl, optionallysubstituted C₆ -C₁₀ aryl or optionally substituted heterocyclic.
 4. Thecompound of claim 3, wherein R¹ is R¹² --CO--, R¹² --O--CO-- or R¹²--NH--CO-- (in which R¹² is C₁ -C₁₅ alkyl optionally substituted by oneor more substituents selected from the consisting of C₃ -C₁₀ cycloalkyloptionally substituted C₃ -C₁₄ aryl, optionally substituted C₆ -C₁₄aryloxy, optionally substituted C₆ -C₁₄ arylthio, optionally substitutedC;hd 7-C₂₀ aralkyloxy, optionally substituted heterocyclic and oxo, oroptionally substituted C₆ -C₁₀ aryl); and R³, R⁵ and R⁷ each isindependently hydrogen, C₁ -C₁₅ alkyl optionally substituted by C₃ -C₁₀cycloalkyl, C₃ -C₁₀ cycloalkyl or C₇ -C₂₀ aralkyl.
 5. The compound ofclaim 4, wherein R¹ is R¹² --O--CO-- (in which R¹² is C₁ -C₁₅ alkyloptionally substituted by one or more substituents selected from theconsisting of C₃ -C₁₀ cycloalkyl, C₆ -C₁₄ aryl and heterocyclic, or C₃-C₁₀ cycloalkyl; R⁴ and R⁶ each is hydrogen, R¹¹ is hydrogen, C₁ -C₁₅alkyl optionally substituted by C₃ -C₁₀ cycloalkyl, C₃ -C₁₀ cycloalkyl,C₇ -C₂₀ aralkyl or C₆ -C₁₀ aryl; and n is
 0. 6. The compound of claim 4,wherein R¹ is R² --O--CO-- (in which R¹² is C₁ -C₁₅ alkyl optionallysubstituted by one or more substituents selected from the groupconsisting of C₃ -C₁₀ cycloalkyl, C₆ -C₁₄ aryl and heterocyclic); R⁴ andR⁶ each is hydrogen, R⁵ and R⁷ each is independently hydrogen, C₁ -C₁₅alkyl optionally substituted by C₃ -C₁₀ cycloalkyl or C₇ -C₂₀ aralkyl;R⁹ is hydroxyl; R¹¹ is optionally substituted heterocyclic; and n is 0.7. The compound of claim 3, wherein R¹ is R¹² --SO₂ --; and R¹¹ ishydrogen, optionally substituted C₆ -C₁₀ aryl or optionally substitutedheterocyclic.
 8. The compound of claim 7, wherein R¹² is optionallysubstituted C₆ -C₁₀ aryl or optionally substituted heterocyclic.
 9. Apharmaceutical composition which comprises, as an active ingredient, acompound of claim 1 together with pharmaceutically acceptable carriers.